RESUMEN
AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.
Asunto(s)
Hemofilia A/complicaciones , Centers for Disease Control and Prevention, U.S. , Preescolar , Recolección de Datos , Femenino , Hemofilia A/epidemiología , Humanos , Lactante , Recién Nacido , Masculino , Estados UnidosRESUMEN
Central venous access devices (CVAD) are increasingly being used for optimal delivery of clotting factor concentrates in patients with haemophilia with poor peripheral venous access. The utility of CVAD is particularly well recognized in young patients starting factor prophylaxis and in patients with inhibitors undergoing immune tolerance induction (ITI). A catheter-related infection (CRI) remains the most common complication of CVAD in haemophilia patients and is the most frequent indication for its removal. Additionally, in some patients the infection results in significant morbidity and mortality and also contributes to failure of the ITI regimen. Ethanol-lock therapy (ELT) is a treatment modality that has been used to treat CRI in patients with indwelling catheters for home parenteral nutrition and chemotherapy. The aim of this study was to report the success in treating CRI in haemophilia patients using ELT. Three severe haemophilia A patients undergoing ITI regimen who developed CVAD infections resistant to conventional management with antibiotics were treated by ELT according to the institutional technique. All three patients responded well to ELT with clearance of the CVAD infection. There were no adverse side effects. To our knowledge, this is the first report of ELT in patients with haemophilia. The role of ELT needs to be investigated in larger studies for treatment of CRI in patients with bleeding disorders.
Asunto(s)
Infecciones Relacionadas con Catéteres/prevención & control , Catéteres de Permanencia/efectos adversos , Infección Hospitalaria/prevención & control , Hemofilia A/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/microbiología , Catéteres de Permanencia/microbiología , Niño , Preescolar , Infección Hospitalaria/microbiología , Contaminación de Equipos/prevención & control , Etanol/farmacología , Hemofilia A/microbiología , Humanos , MasculinoRESUMEN
Haemophilia B is an X-linked disorder resulting in coagulation factor IX deficiency. Patients with severe deficiency (<1% factor IX activity) may have significant bleeding complications similar to patients with haemophilia A or factor VIII deficiency. The development of inhibitory antibodies to the missing coagulation factor is a major complication in patients with haemophilia. While the incidence of inhibitors in patients with haemophilia A is higher than that in haemophilia B, the occurrence of allergic and or anaphylactic reactions with the development of inhibitors is unique to haemophilia B patients. Since haemophilia B is a rare bleeding disorder and the incidence of inhibitors is an even rarer entity, a registry was established by Dr Indira Warrier under the auspices of the FVIII/FIX subcommittee of the International Society of Thrombosis and Haemostasis, to gather information on the occurrence and characteristics of patients with inhibitors and also the incidence of allergic and anaphylactic reactions in this group of patients. This is the first report from this registry and helps us to gather some insight on haemophilia B patients with inhibitors and complications related to inhibitor development and difficulties with immune tolerance.
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Anafilaxia/inducido químicamente , Anticuerpos/inmunología , Inhibidores de Factor de Coagulación Sanguínea/efectos adversos , Factor IX/efectos adversos , Hemofilia B/inmunología , Tolerancia Inmunológica/inmunología , Anticuerpos/efectos de los fármacos , Inhibidores de Factor de Coagulación Sanguínea/antagonistas & inhibidores , Niño , Preescolar , Factor IX/antagonistas & inhibidores , Hemofilia B/tratamiento farmacológico , Humanos , Incidencia , Lactante , Sistema de RegistrosAsunto(s)
Factores de Coagulación Sanguínea/efectos adversos , Coagulantes/efectos adversos , Contaminación de Medicamentos , Infecciones por VIH/etiología , Hemofilia A/tratamiento farmacológico , Factores de Coagulación Sanguínea/historia , Centers for Disease Control and Prevention, U.S./historia , Coagulantes/historia , Adhesión a Directriz , Infecciones por VIH/historia , Hemofilia A/historia , Historia del Siglo XX , Humanos , Guías de Práctica Clínica como Asunto , Estados UnidosRESUMEN
Haemophilia and inherited bleeding disorders in newborns and their carrier mothers pose unique challenges. The pattern of bleeding and the causes and risk factors for bleeding are decidedly different than an older child or an adult with haemophilia/inherited bleeding disorder. This document outlines the needs for further research and education, summarizes the state of the art background information and provides guidance regarding research, education and access to care issues in this population.
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Hemofilia A/genética , Hemorragia/genética , Adulto , Comités Consultivos , Factores de Coagulación Sanguínea/uso terapéutico , Parto Obstétrico/métodos , Femenino , Tamización de Portadores Genéticos/métodos , Terapia Genética/métodos , Hemofilia A/diagnóstico , Hemofilia A/terapia , Hemorragia/diagnóstico , Hemorragia/terapia , Humanos , Recién Nacido , Hemorragias Intracraneales/diagnóstico , Hemorragias Intracraneales/terapia , Embarazo , Diagnóstico Prenatal/métodos , InvestigaciónRESUMEN
BACKGROUND: Deletion of the B-domain of recombinant blood coagulation factor VIII (BDDrFVIII) increases the manufacturing yield of the product but does not impair in vitro or in vivo functionality. BDDrFVIII (ReFacto) has been developed with the additional benefit of being formulated without human albumin. OBJECTIVE: The primary objective of this three-way crossover-design study was to compare the pharmacokinetic (PK) parameters of two BDDrFVIII formulations (one reconstituted with 5 mL of sterile water, the other reconstituted with 4 mL sodium chloride 0.9% USP) with those of a plasma-derived, full-length FVIII preparation (Hemofil M) in patients with haemophilia A to determine bioequivalence. METHODS: A series of blood samples were collected over a period of 48 h after i.v. administration of each of the FVIII preparations. Plasma FVIII activity was determined using a validated chromogenic substrate assay. Plasma FVIII activity vs. time curves was characterized for a standard set of PK parameter estimates. Two parameter estimates, the maximum plasma concentration (Cmax) and the area under plasma concentration vs. time curves (AUCs), were used to evaluate bioequivalence. The two preparations were considered bioequivalent if the 90% confidence intervals for the ratio of geometric means for Cmax and AUCs fell within the bioequivalence window of 80% to 125%. RESULTS/CONCLUSION: Results show that each BDDrFVIII formulation is bioequivalent to Hemofil M and the two formulations of BDDrFVIII are bioequivalent to each other.
Asunto(s)
Factor VIII/farmacocinética , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anticuerpos Monoclonales , Área Bajo la Curva , Estudios Cruzados , Factor VIII/efectos adversos , Factor VIII/análisis , Hemofilia A/inmunología , Hemofilia A/metabolismo , Humanos , Plasma , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacocinética , Método Simple Ciego , Equivalencia TerapéuticaRESUMEN
The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.
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Factor IX/uso terapéutico , Factor VIII/uso terapéutico , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Esquema de Medicación , Servicio de Urgencia en Hospital/estadística & datos numéricos , Hemartrosis/etiología , Hemofilia A/complicaciones , Hemofilia B/complicaciones , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: B-domain-deleted recombinant factor VIII (BDDrFVIII) was developed when the B-domain was found to be redundant for maintaining haemostasis. This allows formulation of the final product without albumin added as a stabilizer. METHODS: Three multicentre clinical studies and one pharmacokinetic study were conducted in 218 patients to evaluate the safety and haemostatic efficacy of BDDrFVIII. RESULTS: Previously treated patients (n = 113; median duration, 1711 days; median exposure days, 385; total 98,096,287 IU infused) rated 97-99% of all infusions as good or excellent efficacy. FVIII inhibitor was noted in one patient in the previously treated patient cohort after 113 exposure days. Among 101 previously untreated patients, responses to BDDrFVIII were rated as excellent or good in 92-95% of infusions (median duration, 1413 days; median exposure days, 148; total 12,636,458 IU infused). Thirty-two previously untreated patients developed inhibitors after a median duration of 12 exposure days (range, 3-49). Sixteen of 32 (50%) patients had low levels (< or = 5 Bethesda units) and 16 had high levels of inhibitors. Inhibitors disappeared in six of 14 (43%) of the high-level and six of eight (75%) of the low-level patients who underwent immune tolerance induction therapy. A total of 42 patients underwent surgery and the overall efficacy of BDDrFVIII was rated as excellent or good for 99.6% of infusions. CONCLUSIONS: The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full-length FVIII concentrates.
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Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Adulto , Anciano , Autoanticuerpos/sangre , Niño , Esquema de Medicación , Factor VIII/antagonistas & inhibidores , Factor VIII/inmunología , Hemostasis Quirúrgica/métodos , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa/métodos , Estudios Prospectivos , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/inmunología , Resultado del TratamientoRESUMEN
The development of an inhibitor antibody to factor VIII (or factor IX) in a child with haemophilia presents a major challenge to the paediatric haematologist. This article provides an overview of the incidence of inhibitor development in early childhood (30-52% in boys with severe haemophilia A), genetic risk factors, detection, high titre, low titre and transient inhibitors, and management. Treatment of patients with inhibitors is time-consuming and expensive. One should make every attempt to ensure that the boy's family has an understanding of inhibitors, treatment options, and just what is being recommended for their child and what this involves. Immune tolerance induction is successful in approximately 85% of boys with factor VIII inhibitors, but in only 40-50% of those with factor IX inhibitors. For treatment of bleeding episodes in children with high-titre (> or = 5 Bethesda Units) inhibitors, therapeutic options include activated prothrombin complex concentrates (APCC), rF VIIa, and (for factor VIII inhibitors) porcine factor VIII. The advantages and disadvantages of each are discussed. Although factor IX inhibitors are far less common (occurring in 2-3% of boys with haemophilia B), approximately 50% are accompanied by the occurrence of anaphylaxis or severe allergic reactions to any factor IX-containing product.
Asunto(s)
Anticuerpos/sangre , Factor IX/inmunología , Factor VIII/inmunología , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Animales , Niño , Factor VIII/uso terapéutico , Hemofilia B/tratamiento farmacológico , Hemofilia B/inmunología , Hemorragia/etiología , Hemorragia/terapia , Humanos , Tolerancia Inmunológica , Masculino , PorcinosRESUMEN
Inhibitor antibodies directed against factor VIII or factor IX present challenges to the clinician. Fortunately, several management options are available, although each has disadvantages as well as advantages. Alloantibodies against factor VIII (which develop in 25 to 50% of children with severe hemophilia A, as well as in a small percentage of children with mild or moderate hemophilia A) may be low titer and transient or may be high titer. Most patients with high-titer problematic inhibitors now try to eliminate the inhibitor by using one of several immune tolerance induction (ITI) regimens. For treatment of bleeding episodes in patients who have high-titer (> or = 5 Bethesda units) inhibitors, one can use a prothrombin complex concentrate (PCC) (preferably an activated PCC [APCC]), recombinant (r) factor VIIa, or porcine factor VIII. The choice of product is generally dependent on the type and severity of the patient's bleeding, degree of cross-reactivity of the patient's inhibitor with porcine factor VIII, physician familiarity with the product, product availability, and cost. In persons with hemophilia B, alloantibodies occur in only 1 to 3% of severely affected individuals. However, in roughly half of those who develop inhibitors, anaphylaxis or severe allergic reactions occur on infusion of any type of factor IX-containing product. This phenomenon usually develops after relatively few exposures to factor IX; thus it is recommended that the first 10 to 20 infusions of factor IX given to children with severe hemophilia B be given in a setting equipped for treatment of shock. For treatment of bleeding episodes in patients with severe allergic reactions, rF VIIa is the treatment of choice. ITI has been less successful in hemophilia B patients with inhibitors than in those with hemophilia A, and in a subgroup of patients with severe allergic reactions who were desensitized to factor IX and then tried on ITI, results were even poorer. Additionally, several developed nephrotic syndrome while on ITI. For hemophilia B patients with inhibitors who do not have allergic reactions to factor IX, bleeding episodes can be treated with PCC or APCC or with rF VIIa. Autoantibodies directed against factor VIII are rare but can occur in a variety of settings. They occur mainly in adults, and bleeding is often severe and life threatening. Although some factor VIII autoantibodies disappear spontaneously, most require immunosuppression. Corticosteroids and cyclophosphamide are generally recommended. For treatment of bleeding, therapeutic options include (human) factor VIII concentrates, porcine factor VIII, APCC, and rFVIIa. The choice of product is generally determined by the consulting hematologist's familiarity with the product, product availability and cost, as well as response to treatment.
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Factor IX/inmunología , Factor VIII/inmunología , Isoanticuerpos/efectos adversos , Animales , Manejo de la Enfermedad , Hemofilia A/inmunología , Hemofilia A/terapia , Hemofilia B/inmunología , Hemofilia B/terapia , Hemorragia/tratamiento farmacológico , HumanosRESUMEN
In hemophiliacs without inhibitors, response to treatment for joint and soft tissue bleeding is much more effective when factor VIII is given early. The same is true in hemophiliacs with inhibitors treated with recombinant activated factor VII (rFVIIa; NovoSeven) for peripheral muscular hemorrhages. In the present report, we analyzed the responses to rFVIIa given to treat acute hemarthroses. We compared the amount of rFVIIa used in the treatment of acute hemarthroses in persons with hemophilia A and B with inhibitors and those with acquired hemophilia in the compassionate use, dose-finding, and United States (US) home treatment studies. We also compared the response rates in each of these studies. As in previous analyses for intramuscular hemorrhages, the average number of doses given for acute joint bleeding was significantly less when treatment was instituted early (as in the US home treatment study). Response rates were also much greater in the US home treatment study than in the dose-finding or compassionate use databases. It is clear that early treatment of acute hemarthroses with rFVIIa results in a greater rate of success, with fewer doses of product being required. Home treatment with rFVIIa results in greater convenience, cost savings and reduced morbidity.
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Factor VIIa/administración & dosificación , Hemartrosis/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Proteínas Recombinantes/administración & dosificación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.
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Factor VIII/inmunología , Hemofilia A/tratamiento farmacológico , Tolerancia Inmunológica/efectos de los fármacos , Isoanticuerpos/sangre , Niño , Preescolar , Estudios de Cohortes , Factor VIII/administración & dosificación , Salud de la Familia , Hemofilia A/complicaciones , Hemofilia A/inmunología , Humanos , Lactante , Isoanticuerpos/uso terapéutico , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Factores de RiesgoRESUMEN
Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection through exposure to blood products. Havrix(R), an intramuscular hepatitis A vaccine, is currently recommended for the prevention of disease caused by hepatitis A virus. Because bleeding may complicate intramuscular injections in those with bleeding disorders, we conducted a randomized, Phase IV clinical trial to compare the safety and immunogenicity of Havrix(R) given by the subcutaneous (s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6 months. All children were anti-HAV and anti-HIV negative at baseline, and the haemophilic group did not differ from their siblings in alanine aminotransferase (ALT; 25 IU L-1 vs. 22 IU L-1), or in age; 8.5 years vs. 8.7 years. The vaccine was well tolerated, with minor adverse events being similar between groups; 21 (47%) vs. 24 (58%), P > 0.05. Local symptoms included soreness in 39 (45%), erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no differences between groups. The proportion seroconverting to anti-HAV IgG positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre was lower in those with Haemophilia, 185 vs. 233 mIU mL-1 at month 1; 68 vs. 94 mIU mL-1 at month 6; and 584 vs. 1082 mIU mL-1 at month 8, respectively. We conclude that Havrix(R) is safe and immunogenic when administered s. c. in children with Haemophilia.
Asunto(s)
Seguridad de Productos para el Consumidor/normas , Vacunas contra Hepatitis Viral/administración & dosificación , Vacunas contra Hepatitis Viral/inmunología , Adolescente , Niño , Preescolar , Contusiones/etiología , Eritema/etiología , Factor VIII/inmunología , Factor VIII/uso terapéutico , Femenino , Fiebre/etiología , Cefalea/etiología , Vacunas contra la Hepatitis A , Anticuerpos Antihepatitis/sangre , Humanos , Tolerancia Inmunológica , Inmunoglobulina G/sangre , Inflamación/etiología , Inyecciones Intramusculares/efectos adversos , Inyecciones Subcutáneas/efectos adversos , Isoanticuerpos/sangre , Masculino , Dolor/etiología , Estudios Prospectivos , Equivalencia Terapéutica , Factores de Tiempo , Vacunas contra Hepatitis Viral/farmacocinéticaRESUMEN
In the short time span since the cloning of the human genes for factors VIII, IX and VII, recombinant factor (rF)VIII, rFIX and rFVIIa concentrates have been produced and standardised, have entered clinical trials, and have been licensed for clinical use in the US, Europe and elsewhere. Even more recently, a new generation of recombinant clotting factor concentrates has emerged, including rFVIII concentrates formulated with sucrose rather than human serum albumin and a B-domain-deleted rFVIII preparation. Additionally, rFVIII concentrates which contain no human or animal proteins in their manufacture are in development, as is a combination rFVIII plus recombinant von Willebrand factor concentrate. The clinical experience in previously treated patients with each of the existing recombinant products has documented that inhibitor development is not increased with any of them. As expected, there has been no reported instance of disease transmission with any of the recombinant clotting factor concentrates. Since their introduction, usage of each of the recombinant clotting factor concentrates has dramatically increased in countries where these products are licensed, available and affordable.
RESUMEN
BACKGROUND AND OBJECTIVES: During the late 1980s, short-term hepatitis safety trials with certain new high purity, virally attenuated plasma derived factor VIII (FVIII) concentrates showed a higher than anticipated percentage of inhibitors in previously untreated patients (PUPs). Thus, the design of prelicensure dinical trials with each of the recombinant (r) FVIII products included prospective evaluations for inhibitors at well-defined time points, to see whether treatment with rFVIII resulted in a higher incidence of inhibitors. DESIGN AND METHODS: Each of several prospective clinical trials with rFVIII preparations is described and analyzed in terms of inhibitor development, patient demographics, and current prevalence of inhibitors in the cohort. RESULTS: In prospective trials with rFVIII preparations (both full length and B domain deleted rFVIII), the percentage of PUPs with severe hemophilia A who developed FVIII inhibitors has varied between 28.3 and 30.6%. Many of the inhibitors have been transient, disappearing while the patient was receiving episodic (on demand) treatment with rFVIII, while others have responded to immune tolerance induction regimens with rFVIII alone. However, many other have persisted. Genetic influences (underlying gene defect and race) were shown to play a role in inhibitor development. In contrast to the experience in the PUPs, in trials with rFVIII preparations in previously treated patients (PTPs), only 0-1 subject per trial developed an inhibitor. INTERPRETATION AND CONCLUSIONS: While the percentage of PUPs developing inhibitors in each of the prospective clinical trials with rFVIII preparations appears high, published data from similarly conducted studies with plasma-derived FVIII products show very similar results. Additionally, only an occasional PTP on rFVIII developed an inhibitor. Thus, none of the rFVIII preparations studied to date appears to be more immunogenic than plasma-derived FVIII.