Hemophilia Gene Therapy: Another Blessing or Another Curse?

Medical therapies for hemophilia patients over the past 60 years have included several blessings and a curse. The long-sought cure with gene therapy may have finally arrived. Unfortunately, preclinical animal models are now raising concerns for genotoxicity with gene therapy. Although no cancers have been detected in humans, it may be a few decades before we know if gene therapy for hemophilia is another blessing, or another curse.

Emergent data influences the risk/benefit assessment of hemophilia gene therapy using recombinant adeno-associated virus.

After decades of investigation, gene therapy has received regulatory approval to treat hemophilia. However, since gene therapy investigations were initially conceived, other avenues of treatment have revolutionized the care of hemophilia. Emergent data is showing that gene therapy may not be as beneficial as hoped and more toxic than planned. At a minimum, a reassessment of risk/benefit estimate of gene therapy for hemophilia is needed.

Factor activity levels and bleeding scores in pediatric hemophilia carriers enrolled in the ATHNdataset.

BACKGROUND: Multiple studies have now shown that a significant proportion of hemophilia carriers meet the criteria for having hemophilia and/or report abnormal bleeding. However, to date, investigations of hemophilia carriers have almost exclusively involved women over 18 years of age. Little is known about factor activity levels and bleeding scores in carriers during childhood. We queried a large deidentified database of subjects with bleeding disorders residing in the United States to determine factor activity levels and bleeding scores. PROCEDURES: The ATHNdataset was queried for hemophilia carriers under 18 years of age. Collected information included demographics, factor activity levels, and bleeding scores. RESULTS: Over 700 carriers in the pediatric age group were identified, of which 626 submitted factor activity levels. Nearly half had factor activity levels less than 40 IU/dL, thereby meeting criteria for having hemophilia. Of those reporting bleeding scores, only 13.5% reported an abnormal bleeding score for age. The proportion reporting abnormal bleeding scores was higher in those with factor levels less than 40 IU/dL (23%) than those greater than 40 IU/dL (9.7%). CONCLUSIONS: The proportion of pediatric carriers with hemophilia was double of that previously reported for adults. Of those with hemophilia reporting a bleeding score, the majority (77%) did not report an abnormal bleeding score for age. However, nearly 10% of pediatric carriers not meeting criteria for having hemophilia reported abnormal bleeding scores for age. Similar results are reported in adults suggesting that factor activity levels may not be predictive of bleeding symptoms in carriers.

Descriptive analysis of bleeding symptoms in haemophilia carriers enrolled in the ATHNdataset.

BACKGROUND: Several studies have reported that haemophilia carriers have a bleeding tendency independent of factor activity. However, investigations have been fraught with methodological concerns. The ATHNdataset houses the largest data set of haemophilia carriers in the world. We undertook an analysis of haemophilia carriers in this data set using methodologies that characterize bleeding symptoms in carriers. AIM: Determine the proportion of haemophilia carriers who have a normal bleeding score (BLS) and factors that affect the BLS. METHODS: The ATHNdataset was queried for haemophilia carriers with a documented BLS. Collected data included demographics, ISTH-BAT score, factor activity level, type of haemophilia (A or B), genotype and geographic residence. RESULTS: Nine hundred twenty-two haemophilia carriers in the ATHNdataset reported a BLS. When adjusted for age, 74% reported a normal score. Logistic regression identified age, factor activity level, ethnicity and region of residence as risk factors for an abnormal score. CONCLUSIONS: The majority of haemophilia carriers (74%) in the ATHNdataset had a normal BLS, including the majority (59%) with factor activity levels < 40 IU/dl. Conversely, 24% of haemophilia carriers with a factor activity level > 40 IU/dl reported an abnormal BLS. These results are consistent with previous studies of haemophilia carriers. Additional investigation is needed to determine why a majority of haemophilia carriers with low factor activity levels report normal BLSs while a significant minority of haemophilia carriers with normal activity levels report abnormal BLSs.

Normal aPTT in children with mild factor XI deficiency.

It has been suggested that persons with factor XI deficiency can have a normal activated partial thromboplastin time (aPTT). This notion is based on limited data, especially in children. Because of the central role the aPTT plays in diagnostic algorithms for bleeding disorders, it is important to know if a normal aPTT eliminates the need for factor XI activity testing. Our institutional database contains seven children with factor XI deficiency, of whom four have a normal aPTT. This supports the hypothesis that children with factor XI deficiency can have a normal aPTT. Clinicians may wish to consider this evidence when evaluating children with abnormal bleeding.

Widespread use of fresh frozen plasma in US children's hospitals despite limited evidence demonstrating a beneficial effect.

OBJECTIVES: To determine the pattern, prevalence and potential complications of fresh frozen plasma (FFP) use in US pediatric hospitals from 2002-2009. STUDY DESIGN: Retrospective cohort study using the Pediatric Health Information System (PHIS) administrative database, which was queried for FFP admissions using diagnostic, procedural, and billing codes. Demographic data, daily use, and procedural codes were used to describe the patient population and pattern of FFP use. RESULTS: Of 3 252 149 PHIS-recorded admissions, 2.85% had codes consistent with FFP use. This percentage did not change over the course of the study (P=.10). FFP was most commonly administered to children <1 year of age (54%), critically ill children (70%), and those with heart disease (34%). Fifteen percent of FFP-related admissions involved a thrombotic event. The overall mortality rate was 17% and it decreased during the study (P<.001). There was noteworthy variation in the proportion of FFP admissions among participating institutions. CONCLUSIONS: FFP is commonly used in children admitted to PHIS hospitals. Despite recent expert recommendations highlighting the lack of efficacy in many clinical scenarios, the rate of FFP use does not appear to be changing. Randomized, controlled studies are needed to determine appropriate indications for FFP use and evaluate for potential complications.

Optimal use of recombinant factor VIIa in the control of bleeding episodes in hemophilic patients.

One of the last remaining clinical hurdles in the treatment of people with hemophilia is the development of inhibitors. Alloantibodies or autoantibodies directed at coagulation factors render the infusion of coagulation factor concentrates ineffective, and alternative means must be used to achieve hemostasis. Recombinant factor VIIa (rFVIIa) was developed to control bleeding episodes in hemophilic patients with inhibitors. Clinical efficacy in achieving hemostasis in inhibitor patients was demonstrated by a compassionate-use protocol, as well as in randomized controlled trials. To date, over 1.5 million doses of rFVIIa have been given to inhibitor patients, with an excellent efficacy and safety record. Because of its short half-life, alternative means of dosing and infusing rFVIIa have been explored and are reviewed here.

Fresh frozen plasma and recombinant factor VIIa use in neonates.

BACKGROUND: Little recent data are available describing fresh frozen plasma (FFP) use in neonates. The purpose of this study was to determine the outcomes of FFP transfusions in neonates. PATIENTS AND METHODS: A single institution, observational, and retrospective review of each transfusion of FFP given to neonates admitted to a neonatal intensive care unit over a 2-year period. RESULTS: One hundred and seventy-three neonates were identified as having received FFP, giving a prevalence of FFP use at 12%. By far the most common determining factor for FFP use was an association with an abnormal activated partial thromboplastin time or prothrombin time (52%). Other factors included bleeding, invasive procedures, volume expansion, necrotizing enterocolitis, cardiopulmonary bypass, and hydrops fetalis. Of objectively accessible responses, FFP was able to correct abnormal coagulation tests into the normal range only 40% of the time. Twenty-four neonates received recombinant factor VIIa (rFVIIa) after first receiving FFP. The prevalence of thrombotic events was not higher in neonates receiving rFVIIa than those receiving FFP alone. CONCLUSIONS: FFP was widely used in this neonatal unit. As data showing the predictive value of coagulation tests in neonates are discrepant, it is unclear if FFP was being appropriately used. Prospective, controlled data are required.

Thrombotic events in neonates receiving recombinant factor VIIa or fresh frozen plasma.

BACKGROUND: Numerous recent reports have described the use of recombinant factor VIIa (rFVIIa) in non-hemophilia bleeding situations for achievement of hemostasis. However, its use in clinical situations other than hemophilia patients with inhibitors has been complicated by some reports of thrombotic events. rFVIIa has been used successfully to treat coagulopathic and/or bleeding neonates. The prevalence of thrombotic events in these neonates is completely unknown. This study was initiated to determine the risk of thrombotic events associated with rFVIIa use in neonates. PROCEDURE: All published literature in non-hemophilic, non-congenital factor VII deficient neonates receiving rFVIIa was reviewed. In addition, all data submitted to the SeveN Bleep Registry, a web-based registry of rFVIIa uses in non-hemophilic children was analyzed. As the baseline risk of thrombotic events in bleeding and/or coagulopathic neonates is not known, we also reviewed the records of 100 consecutive neonates from a single institution who received fresh frozen plasma (FFP) alone to treat their coagulopathy and/or bleeding episode. RESULTS: A total of 134 neonates received rFVIIa. Of these, 10 (7.5%) had a thrombotic event. The baseline risk of thrombotic events in neonates receiving FFP was 7%. CONCLUSIONS: Overall the prevalence of thrombotic events in bleeding and/or coagulopathic neonates appears to be around 7%, whether or not they receive rFVIIa.

Platelet function disorder in Gardner-Diamond syndrome: a case report and review of the literature.

The Gardner-Diamond syndrome is a disorder characterized by recurrent spontaneous painful bruising in patients with underlying psychosis and neurosis. Despite the presence of other symptoms suggestive of an underlying disorder of primary hemostasis in a large percentage of reported patients, results of testing for von Willebrand disease or platelet function disorders are lacking. The authors describe a case of Gardner-Diamond syndrome in an adolescent girl who had abnormal platelet responses during platelet aggregation studies. A review of the literature revealed only three additional patients with Gardner-Diamond syndrome who have had platelet aggregation studies reported. To date, all patients with Gardner-Diamond syndrome reported to have undergone platelet aggregation studies have had abnormal results.

Use of recombinant factor vila to control bleeding in an adolescent male with severe hemophilia A, HIV thrombocytopenia, hepatitis C, and end-stage liver disease.

Few options are available to treat hemorrhaging during the palliative care of patients. Blood products, such as plasma and platelets, are difficult to transfuse in the home or hospice setting. What is needed is a product that can be given in the home setting for effective control of hemorrhaging in patients with various types of coagulopathies. Unfortunately, no such product currently exists. One agent that may be beneficial in this clinical setting is recombinant factor VIIa. This factor was approved initially for controlling hemorrhaging in patients with hemophilia who have developed antibodies againstfactor VIII, known as inhibitors. It subsequently has been found to control bleeding in several other clinical situations. We will describe our use of this agent during the palliative care of a patient with numerous insults to his coagulation system.