ABSTRACT
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.
Subject(s)
Hemophilia A/complications , Centers for Disease Control and Prevention, U.S. , Child, Preschool , Data Collection , Female , Hemophilia A/epidemiology , Humans , Infant , Infant, Newborn , Male , United StatesABSTRACT
OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.
Subject(s)
Factor VIII/administration & dosage , Factor VIII/pharmacokinetics , Hemophilia A/therapy , Adolescent , Adult , Animals , Blood Coagulation Factor Inhibitors/blood , Factor VIII/adverse effects , Factor VIII/antagonists & inhibitors , Hemophilia A/blood , Humans , Infusions, Intravenous , Male , Middle Aged , Peptide Fragments/administration & dosage , Peptide Fragments/adverse effects , Peptide Fragments/pharmacokinetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokinetics , Swine , Young AdultSubject(s)
Biomedical Research/trends , Delivery of Health Care/standards , Education, Medical, Continuing/standards , Hemophilia A/therapy , Congresses as Topic , Delivery of Health Care/trends , Education, Medical, Continuing/trends , Hemophilia A/epidemiology , Humans , Multicenter Studies as Topic , Quality of Life/psychology , World Health Organization/organization & administrationABSTRACT
Haemophilia patients with inhibitors characteristically have impaired joint function and reduced health-related quality of life (HRQoL). This analysis examined whether secondary prophylaxis with recombinant activated factor VII (rFVIIa) improves HRQoL vs. conventional on-demand therapy in patients with haemophilia with inhibitors and frequent bleeds. After a 3-month preprophylaxis period, 22 patients received daily rFVIIa prophylaxis (90 or 270 microg kg(-1)) for 3 months, followed by 3 months' postprophylaxis. Days of hospitalization, absence from school/work and mobility aids requirements were recorded. HRQoL was assessed by EuroQoL (EQ-5D) questionnaire, visual analogue scale (VAS), derived Time to Trade-Off (TTO) scores and Quality Adjusted Life Years (QALYs). rFVIIa prophylaxis significantly (P < 0.0001) reduced bleeding frequency vs. prior on-demand therapy. Hospitalization (5.9% vs. 13.5%; P = 0.0026) and absenteeism from school/work (16.7% vs. 38.7%; P = 0.0127) decreased during prophylaxis; these effects tended to be maintained during postprophylaxis. HRQoL (evaluated by EQ-5D) tended to improve during and after rFVIIa prophylaxis. Notably, pain decreased and mobility increased in 40.9% and 27.3% of patients, respectively, at the end of the postprophylaxis period vs. preprophylaxis. Median VAS score increased from 66 to 73 (P = 0.048), and TTO scores suggested better HRQoL (0.62 vs. 0.76; P = 0.054) during postprophylaxis than preprophylaxis. Small to moderate changes in effect sizes were reported for VAS and TTO scores. Median QALYs were 0.68 (VAS) and 0.73 (TTO). Reductions in bleeding frequency with secondary rFVIIa prophylaxis were associated with improved HRQoL vs. on-demand therapy.
Subject(s)
Coagulants/therapeutic use , Factor VIIa/therapeutic use , Hemarthrosis/prevention & control , Hemophilia A/drug therapy , Hemophilia B/drug therapy , Outcome Assessment, Health Care/statistics & numerical data , Adolescent , Adult , Child , Child, Preschool , Hemophilia A/physiopathology , Hemophilia B/physiopathology , Humans , Prospective Studies , Quality of Life , Quality-Adjusted Life Years , Recombinant Proteins/therapeutic useABSTRACT
Arthropathy remains a major cause of morbidity in patients with haemophilia. Frequent bleeding into the joints leads to joint damage with resultant contractures, joint deformities and arthritis. This in turn leads to muscle atrophy, limited physical activity, osteoporosis and disability. Even though several studies of prophylactic factor replacement for persons with severe haemophilia demonstrate improved joint function, this therapy is still not readily available to most people with haemophilia around the world and a universal treatment protocol has not been used. In this article, we discuss key issues in the treatment of severe haemophilia: the optimal timing of initiation and termination of therapy, dosing options and goals of therapy. The options for countries where prophylaxis is not readily available are also discussed. Most studies are small and not randomized making consensus treatment recommendations difficult to formulate. Randomized, clinical trials are needed to provide the answers regarding the optimal treatment of patients with severe haemophilia.
Subject(s)
Hemarthrosis/etiology , Hemophilia A/complications , Synovitis/etiology , Adolescent , Adult , Age Factors , Cartilage, Articular , Child , Child, Preschool , Disease Management , Factor IX/therapeutic use , Factor VIII/therapeutic use , Female , Hemarthrosis/prevention & control , Hemophilia A/drug therapy , Hemophilia A/physiopathology , Humans , Male , Prospective Studies , Randomized Controlled Trials as Topic , Synovitis/complications , Synovitis/drug therapyABSTRACT
Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy.
Subject(s)
Arthritis/prevention & control , Hemarthrosis/etiology , Hemophilia A/complications , Iron/adverse effects , Synovitis/etiology , Animals , Arthritis/physiopathology , Cartilage, Articular , Cytokines/metabolism , Factor IX/therapeutic use , Factor VII/therapeutic use , Female , Hemarthrosis/physiopathology , Hemophilia A/drug therapy , Hemophilia A/physiopathology , Humans , Iron/metabolism , Male , Mice , Models, Molecular , Synovitis/physiopathologyABSTRACT
Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decision-making. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence.
Subject(s)
Blood Coagulation Factor Inhibitors/immunology , Factor IX/antagonists & inhibitors , Factor VIII/antagonists & inhibitors , Hemophilia A/therapy , Immunosuppression Therapy/methods , Catheters, Indwelling , Child, Preschool , Cost-Benefit Analysis , Equipment Failure , Factor IX/administration & dosage , Factor IX/immunology , Factor IX/pharmacokinetics , Factor VIII/administration & dosage , Factor VIII/immunology , Factor VIII/pharmacokinetics , Hemophilia A/immunology , Humans , Infant , Infections/complications , Infections/immunology , Meta-Analysis as Topic , Randomized Controlled Trials as Topic , Risk Factors , Treatment FailureSubject(s)
Disseminated Intravascular Coagulation/diagnosis , Hematologic Tests/standards , Disseminated Intravascular Coagulation/blood , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Humans , Platelet Count , Practice Guidelines as Topic , Predictive Value of Tests , Prognosis , Prothrombin Time , Reference Standards , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.
Subject(s)
Blood Coagulation Factor Inhibitors/antagonists & inhibitors , Hemophilia A/drug therapy , Immune Tolerance/drug effects , Consensus Development Conferences as Topic , Genetic Testing/methods , Hemophilia A/genetics , Hemophilia A/immunology , Humans , Practice Guidelines as Topic , Risk FactorsABSTRACT
The costs of haemophilia-related care and the impact of unusually expensive, or outlier, patients on these costs have been explored in numerous European, American and Canadian studies during the last decade. In particular, antibodies that neutralize infused factor VIII or IX (high-responding inhibitors) make treatment responses, and thereby costs, much less predictable. There is little debate that the health care costs of haemophilic patients with high-responding inhibitors are routinely higher and more variable than those of non-inhibitor patients. However, the extent to which this is attributable to the few outlier inhibitor patients whose expenditures tend to skew the data is not as clear. To compare the variation and range in health care expenditures among patients with inhibitors and those without, we reviewed data originally gathered during a 24-month period in 1995-1997 from a prospectively created cohort as part of a broader cost and utilization study conducted at a large haemophilia treatment centre. We conclude that although the use of outpatient factor replacement products was not significantly greater or more expensive among inhibitor patients, their hospital-related costs greatly increased overall expenditures. Among our study population, the overall costs associated with inhibitor patients are not only higher in absolute monetary terms, but also in terms of the degree of variation. This variation was demonstrated by: (i) the extremely wide range of costs over an extended timeframe among individual inhibitor patients when compared with those without inhibitors, and (ii) the much larger year-to-year variation in costs among the inhibitor group.
Subject(s)
Blood Coagulation Factor Inhibitors/economics , Coagulants/economics , Factor IX/economics , Factor VIII/economics , Hemophilia A/economics , Adolescent , Adult , Child , Child, Preschool , Coagulants/therapeutic use , Cohort Studies , Costs and Cost Analysis , Factor IX/therapeutic use , Factor VIII/therapeutic use , Female , Health Care Costs , Hemophilia A/drug therapy , Humans , Infant , Male , Middle AgedABSTRACT
Although up to 80% of high-responding inhibitors in patients with severe factor VIII deficiency can be eliminated using heterogeneous regimens for immune tolerance induction, the residual morbidity in this population of haemophilic patients is far from trivial. There is an exigent need for focussed basic, translational and clinical research to extend our understanding of the pathogenesis of haemophilic inhibitor development. In this article, we identify four key research needs, including (i) whether presently available clotting factor concentrates (CFCs) have differential antigenicity, giving rise to clinically relevant immunogenicity; (ii) the interplay of quantitative and qualitative (e.g. age at first exposure) influences of CFCs as well as host-environmental factors (e.g. vaccination effects) on inhibitor development; (iii) the therapeutic role (if any) that concurrent immune tolerance with suppressive or immune-competitive therapeutic strategies play in inhibitor eradication and (iv) pending any major therapeutic advances, alternative or enhanced strategies for treating acute haemorrhage and for preventing chronic haemorrhagic events in these patients.
Subject(s)
Blood Coagulation Factor Inhibitors/antagonists & inhibitors , Coagulants/immunology , Factor IX/immunology , Factor VIII/immunology , Hemophilia A/immunology , Blood Coagulation Factor Inhibitors/immunology , Coagulants/therapeutic use , Factor IX/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/drug therapy , HumansABSTRACT
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.
Subject(s)
Hemophilia A/genetics , Hemorrhage/genetics , Adult , Advisory Committees , Blood Coagulation Factors/therapeutic use , Delivery, Obstetric/methods , Female , Genetic Carrier Screening/methods , Genetic Therapy/methods , Hemophilia A/diagnosis , Hemophilia A/therapy , Hemorrhage/diagnosis , Hemorrhage/therapy , Humans , Infant, Newborn , Intracranial Hemorrhages/diagnosis , Intracranial Hemorrhages/therapy , Pregnancy , Prenatal Diagnosis/methods , ResearchABSTRACT
Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.
Subject(s)
Catheterization, Central Venous , Hemophilia A/complications , Catheterization, Central Venous/methods , Catheters, Indwelling , Choice Behavior , Contraindications , Device Removal , Equipment Contamination/prevention & control , Humans , Infection Control , Patient Selection , Postoperative Complications/prevention & control , Risk Assessment , Thrombosis/prevention & controlABSTRACT
This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset of 13 non-emergency patients 7-21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for 107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.