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

INTRODUCTION: Ensuring hemostasis during invasive procedures is a challenge in patients with severe hemophilia A. This analysis evaluated efficacy and safety of BAY 94-9027, an extended-half-life recombinant factor VIII (FVIII), in the surgical setting. MATERIALS AND METHODS: Patients participating in an open-label BAY 94-9027 clinical trial who underwent major surgery were included in the analysis. Investigator/surgeon assessment of hemostasis during surgery was the primary outcome. In addition, information about FVIII use, FVIII levels during perioperative period, bleeding complications and FVIII inhibitor development were collected. RESULTS: Data were analyzed for 26 major surgeries (orthopedic, n = 21) in 20 patients aged 13-61 years. BAY 94-9027 provided effective hemostasis during all procedures. FVIII levels 6-8 h post preoperative infusion and prior to the first follow-up infusion were in the range expected to maintain protection in the major surgery setting. The median time from preoperative infusion to the first follow-up infusion (the first infusion administered after the preoperative infusion) was 12.33 (3.6-49.9) h. No intraoperative bleeding complications occurred, and no new inhibitors developed following any surgery. CONCLUSIONS: The results of the study demonstrate that BAY 94-9027 was efficacious and well tolerated in the treatment of patients undergoing major surgeries. Advantages of BAY 94-9027 include the potential for less frequent infusion and reduced factor consumption, which should simplify the management of patients during major surgery.

Baby hamster kidney cell-derived recombinant factor VIII: a quarter century of learning and clinical experience.

INTRODUCTION: Management and care of individuals with hemophilia A advanced immensely with the introduction of recombinant factor VIII (rFVIII) replacement products. This review provides a historical overview of rFVIII development with a focus on Bayer's rFVIII (with albumin) and sucrose-formulated rFVIII (rFVIII-FS), the only rFVIII products cloned in baby hamster kidney (BHK) cells with >25 years of proven safety and efficacy. Areas covered: We review the advances in rFVIII technology and the efficacy and safety data for BHK-derived rFVIII/rFVIII-FS from clinical trials, investigator-initiated studies, and observational studies. Innovative products with new treatment potentials (eg, BAY 81-8973 and BAY 94-9027) built on this established safety and efficacy profile are also briefly discussed. The literature search strategy included targeted searches (PubMed) with manual article selection and other product-specific searches. Expert commentary: Development of rFVIII products and related improvements in viral safety and manufacturing efficiency have guaranteed an adequate supply of factor products worldwide and increased prophylaxis use. The net effects have been joint health preservation, reduction in morbidity and mortality, and quality-of-life enhancements. Current treatment challenges include lack of adherence to prophylaxis and inhibitor development; extended-half-life rFVIII products and non-FVIII replacement therapies in development may help overcome these challenges.

An overview of current trends and gaps in patient-reported outcome measures used in haemophilia.

AIM: This review summarises the importance, recent progress and issues in measuring patient-reported outcomes (PROs) in haemophilia research. METHODS: A critical review of recent advances and trends in measuring haemophilia-related PROs was conducted, using current regulatory guidelines and methodological recommendations to evaluate these instruments. RESULTS: Although regulators, payers and policymakers increasingly consider the patient's perspective to be important in treatment decision-making, to date, few haemophilia intervention studies have meaningfully applied PRO endpoints. Condition-specific PRO instruments have been developed, but most are not fully validated; sensitivity to subgroup differences and changes over time is unclear. Generic PROs and instruments developed for other conditions have been used to measure health-related quality of life (HRQL) in haemophilia patients, but little evidence of their validity for this purpose exists. Haemophilia presents a number of challenges to developing valid, reliable and responsive PRO instruments, including the rarity of the disorder; necessitating research in multiple counties to attain sufficient sample size; the chronic nature of the condition; acute exacerbations of illness; age and geographical region variations with respect to treatment; differences in treatment regimens, range of disease severity and phenotypes; and changes in patients' perceived health status over time. Given that haemophilia begins at birth, the illness has an impact on the lives of caregivers, although the extent of the impact is largely unknown. CONCLUSIONS: Patient perspectives are crucial to understanding the best and most cost-effective haemophilia treatment approaches. More research is needed on the ability of current disease-specific and generic PRO instruments to capture responsiveness to treatments over time and subgroup differences in outcomes. Inclusion of PROs in clinical trials is necessary to answer these questions.

Illustrating the impact of mild/moderate and severe haemophilia on health-related quality of life: hypothesised conceptual models.

INTRODUCTION/AIMS: Haemophilia and its treatment have a significant impact on patients' lives. The study objectives were to understand the impacts of haemophilia and its treatment from the patient perspective and to inform the development of comprehensive health-related quality-of-life (HRQL) conceptual models to illustrate these impacts. METHODS: The study included two phases. Phase I involved a review of literature published from 1995 to 2010, qualitative analysis of six patient (N = 31) and three healthcare provider (N = 15) focus group transcripts, and interviews with two experts to inform draft conceptual models of mild/moderate and severe haemophilia. Phase II involved interviews with 20 haemophilia patients and qualitative analysis of transcripts to confirm the concepts and structure of the conceptual models. RESULTS: The literature search resulted in 66 publications assessing HRQL, four of which were qualitative studies on the impact of haemophilia from the patient perspective. Results from Phase I indicated that acute bleeding events result in pain, swelling, bruising and restricted joint movement; repeated joint bleeds result in chronic symptoms, such as pain and arthropathy. Acute bleeds cause interruptions in daily activities and interfere with work/school. Patients have fears about having bleeds, which can affect their participation in activities, such as sports or crowded events. Patients also expressed feelings of depression, frustration, isolation and embarrassment. Results of Phase II corroborated findings from Phase I. CONCLUSIONS: The conceptual models illustrate the substantial impact of haemophilia and its treatments on patients' lives and can help inform clinical study design and the selection of endpoints to assess treatment benefit.

Patient-reported experience of bleeding events in haemophilia.

BACKGROUND: Patients with haemophilia experience bleeds because of absent or reduced clotting factor. The study objective was to understand the bleeding experience from the patients' perspective. MATERIALS AND METHODS: Individuals with moderate/severe haemophilia participated in interviews and were asked to describe their most recent bleeding experience, including symptoms, signs of onset, impacts, when bleeding stopped and treatment effectiveness. Interview transcripts were analysed using a thematic analysis involving the coding of transcripts to identify key concepts and themes. RESULTS: Twenty males [10 adults, mean age = 41 (19-52); 10 adolescents, mean age = 13 (12-17)] with moderate (n = 5) or severe (n = 15) haemophilia participated. Symptoms signalling bleed onset included pain, swelling, stiffness, tingling/numbness and/or warmth. Participants reported feeling anger and frustration due to the unpredictable nature, pain and inconvenience of the episode. Adults sometimes reported delaying treatment due to inconvenience or cost; adolescents generally treated right away. Reported bleed severity was influenced by pain level, speed of symptom progression, location, continued use of the affected area, recurrence in same location of recent bleed and treatment delay. Participants reported that it was 'easy' to know when the bleed had stopped. Participants reported that symptoms might linger for days before they returned back to 'normal'. CONCLUSIONS: This qualitative study details the substantial impact of an acute bleed from the patient perspective. Given that treatment was reported to be delayed in part due to inconvenience, more convenient treatment options could help reduce delays in treating bleeds and thereby minimise bleed-related impacts. Clinical studies in haemophilia should include validated patient-reported measurements of acute symptoms and bleed severity to comprehensively assess the bleeding event.

An unusual presentation of May-Thurner syndrome in a pediatric patient with a pelvic kidney.

We report a case of an adolescent who presented with a deep vein thrombosis (DVT) and clinical findings consistent with May-Thurner Syndrome. Specific imaging demonstrated direct compression of the left common iliac vein by an overlying pelvic kidney. The patient's history and clinical presentation is detailed. The discussion focuses on the potential implications for care and management of a patient with an ectopic left pelvic kidney.

Newly diagnosed immune thrombocytopenia in children and adults: a comparative prospective observational registry of the Intercontinental Cooperative Immune Thrombocytopenia Study Group.

BACKGROUND: Primary immune thrombocytopenia is a bleeding diathesis with an unknown etiology in predisposed individuals with immune disturbances. Although it is claimed that children and adults differ in clinical and laboratory aspects, few data exist to corroborate this observation. Our objective was to assess comparative data from children and adults with newly diagnosed immune thrombocytopenia. DESIGN AND METHODS: Clinical and laboratory data of 1,784 children and 340 adults were extracted from the Pediatric and Adult Registry on Chronic Immune Thrombocytopenia. The registry represents a prospective cohort of children and adults with newly diagnosed immune thrombocytopenia. Participating investigators registered their patients immediately after the diagnosis using a web based data transfer. Children aged under 16 years were compared with adults aged 16 years and over with descriptive statistical analyses. RESULTS: The presenting mean platelet count of children and adults was 18.1 and 25.4 × 10(9)/L. Signs of bleeding were reported in 24% of children and in 23% of adults, and intracranial hemorrhage in 10 of 1,784 children and in 6 of 340 adults. Co-morbidity was observed in 3.9% of children and in 30% of adults. Bone marrow aspiration and laboratory tests (antinuclear antibodies, human immunodeficiency and hepatitis C virus) were performed more frequently in adults. Children and adults were followed with a 'watch and wait' strategy in 20% and in 29%, respectively. Immunoglobulins were used more frequently in children and corticosteroids in adults. CONCLUSIONS: Comparative data of children and adults with newly diagnosed immune thrombocytopenia revealed similarities in presenting platelet counts and in bleeding, whereas differences occurred in co-morbidity, diagnostic procedures and therapy.

Deep venous thrombosis in adolescents due to anatomic causes.

Aberrant or anomalous anatomy is an under appreciated risk for venous thromboembolic events (VTE). Five adolescents with VTE and predisposing anatomic abnormalities are presented. In three cases, knowledge of the underlying anatomic abnormalities resulted in changes in treatment and management. In two other cases, failure to consider or correct the underlying defect resulted in recurrent thrombosis or post-thrombotic complications. Few case reports are found in the pediatric literature, but a MEDLINE search across all age groups suggests these anomalies are frequently found when appropriate radiological imaging is obtained.

Prophylactic treatment of a small child with severe factor VII deficiency using repeat dosing from a single vial of recombinant activated factor VII.

We report our experience with a small child with severe factor VII deficiency and a history of frequent and spontaneous life-threatening hemorrhage. The patient has received several years of successful prophylactic treatment with an every 3-day infusion program in which she receives recombinant activated factor VII (rVIIa) using multiple doses from a single reconstituted vial over a 72-hr period. Comparison is made to prophylactic treatment in this same patient using plasma-derived factor VII (PDVII) using a prothrombin complex concentrate (PCC).

Combined venous sinus angioplasty and low-dose thrombolytic therapy for treatment of hemorrhagic transverse sinus thrombosis in a pediatric patient.

We describe the successful treatment of a 5-year-old girl with rapidly evolving left hemispheric hemorrhagic infarcts resulting from left transverse and sigmoid sinus thrombosis using combined endovascular dural sinus angioplasty and local low-dose thrombolytic therapy.

Age and the prevalence of bleeding disorders in women with menorrhagia.

OBJECTIVE: A study was conducted to evaluate the frequency and types of hemostatic defects occurring in adolescent and perimenopausal-age women diagnosed with menorrhagia. METHODS: A total of 115 women with a physician diagnosis of menorrhagia, including 25 adolescent women, 25 perimenopausal-age women, and 65 women between the ages of 20 and 44, underwent comprehensive hemostatic testing for possible bleeding disorders. Frequencies of bleeding disorders were calculated and compared. RESULTS: Forty-seven percent of women were found to have hemostatic abnormalities, including platelet dysfunction, von Willebrand's disease, and coagulation factor deficiencies. Adolescents and perimenopausal-age women with menorrhagia were just as likely to have hemostatic abnormalities as were women aged 20 to 44. CONCLUSION: These results demonstrate that underlying bleeding disorders are frequently found in adolescent, postadolescent reproductive age, and perimenopausal-age women presenting with menorrhagia and suggest that women with menorrhagia should be considered for further hemostatic evaluation.

Low molecular weight heparin in the treatment of venous and arterial thromboses in the premature infant.

OBJECTIVE: Thrombosis in the preterm newborn is a growing problem, a result of improved survival of the smallest and sickest infants. Treatment with low molecular weight heparin (LMWH) has potential advantages, including predictable pharmacokinetics, subcutaneous administration, and minimal monitoring. However, studies with LMWH in term infants demonstrate the need for higher doses as compared with older children and adults. Physiologic differences suggest the need for gestational age-appropriate treatment strategies. Because of the relatively small numbers of infants affected each year, large-scale prospective studies have not been feasible. With the goal of establishing treatment guidelines within our own institution, we reviewed retrospectively our experience with LMWH for the treatment of thrombosis in the preterm infant. METHODS: Medical and pharmacy records of the intensive care nursery were used to identify preterm infants with venous and arterial thrombosis. Chart documentation, orders, pharmacy records, and radiologic studies were used to develop a retrospective database to assess efficacy and safety of the treatment. Main outcome measures were the dose of LMWH required for therapeutic levels, anti-factor Xa levels achieved, bleeding complications, resolution of thrombosis, additional thromboembolic events, and death from all causes. RESULTS: Ten preterm infants (mean gestational age: 26 weeks) who were treated with LMWH were identified. Mean patient weight at diagnosis of thrombosis was 1215 g (range: 565-1950 g). All 10 patients had either a current or recent history of a central venous or arterial catheter. Mean starting dose of enoxaparin was 1.25 mg/kg per 12 hours (range: 0.8-2 mg/kg). Therapeutic anti-factor Xa levels were achieved in only 5 patients. Mean time to therapeutic range was 33 days (range: 14-63 days). The mean dose of enoxaparin required to achieve therapeutic levels was 2.27 mg/kg per 12 hours (dose range: 2.0-3.5 mg/kg per 12 hours). Clot resolution was observed in all but 2 patients, both of whom died of complications of their thromboembolic events. No bleeding events that necessitated a change in treatment strategy occurred. CONCLUSIONS: Higher doses of LMWH are required in the preterm infant as compared with the healthy term neonate. Once therapeutic levels are achieved, continued regular monitoring and dose adjustments are required to maintain anticoagulation in therapeutic range.

A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the Intercontinental Childhood ITP Study Group.

OBJECTIVE: To analyze prospectively the impact of age at diagnosis in childhood idiopathic thrombocytopenic purpura (ITP). STUDY DESIGN: International registry from June 1997 to May 2001, with analysis of data from baseline and 6-month-follow-up questionnaires. RESULTS: Data from 2540 patients were analyzed, including 203 infants (7.6%), 1860 children > or =1 to <10 years of age (69.1%), and 477 children and adolescents between > or =10 and <16 years of age (17.7%). The mean platelet count at diagnosis was similar in all three groups, as was the percentage of patients with initial platelet count <20x10(9)/L. The male/female ratio was highest in infants and decreased with age (P=.009). Immunoglobulin therapy was used more often in infants and corticosteroids in patients > or =10 years of age. Follow-up information at 6 months was available for 1742 children (68.6%). Chronic ITP was seen less frequently in infants (23.1%) than in children >10 years of age (47.3%, P<.0001). Intracranial hemorrhage occurred in 3 of 1742 children during the first 6 months after the diagnosis of ITP. CONCLUSIONS: Pediatric patients with ITP from infancy to adolescence exhibit heterogeneity in clinical, demographic, and treatment factors.