Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.

Evidence suggests greater doses of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) than currently administered may result in enhanced haemostasis and convenience for patients with haemophilia A and B with inhibitors. This study evaluated efficacy and safety of rFVIIa and an activated prothrombin complex concentrate (APCC; Factor Eight Inhibitor Bypassing Activity [FEIBA], Baxter AG, Vienna, Austria) for controlling joint bleeds in a home-treatment setting. Patients received each of three treatments in one of six possible sequences: 270 microg kg(-1) rFVIIa at hour 0 + placebo at hours 3 and 6, 90 microg kg(-1) rFVIIa at hours 0, 3 and 6, and 75 U kg(-1) APCC at hour 0. Efficacy was assessed by the requirement for additional haemostatics within 9 h and by a novel global response algorithm. The percentage of rFVIIa 270 microg kg(-1) group patients requiring additional haemostatics within 9 h (8.3%) was significantly lower than that for the APCC group (36.4%, P = 0.032). The percentage of rFVIIa 90 x 3 microg kg(-1) group patients requiring such rescue medication (9.1%) was also lower compared to the APCC group. This result approached, but did not reach statistical significance (P = 0.069). Both rFVIIa treatment groups showed similar use of rescue medication (8.3% and 9.1% of episodes for rFVIIa 270 microg kg(-1) and rFVIIa 90 x 3 microg kg(-1) groups respectively). No significant differences in treatment response were observed with the global response algorithm (P = 0.173). No safety issues were identified. A single dose of rFVIIa 270 microg kg(-1) is as safe and effective as rFVIIa 90 x 3 microg kg(-1) dosing, and may be considered a potentially more effective alternative to APCCs for the management of joint bleeding in this population.

Human coagulation factor FVIIa (recombinant) in the management of limb-threatening bleeds unresponsive to alternative therapies: results from the NovoSeven emergency-use programme in patients with severe haemophilia or with acquired inhibitors.

This open-label, emergency-use study evaluated the efficacy and safety of activated human coagulation factor VIIa (recombinant) (rFVIIa) (NovoSeven; Novo Nordisk Pharmaceuticals, Inc., New Jersey, USA) in treating limb-threatening joint or muscle bleeds in 17 patients with haemophilia A or B and six patients with acquired inhibitors to factor VIII or factor IX. All patients had previously failed on one or more alternative therapies. rFVIIa administration was effective or partially effective in controlling joint or muscle bleeds in 34 out of 35 (97%) bleeding episodes; in 23 patients, 14 of 17 (82%) muscle bleeds and 16 of 18 (89%) joint bleeds were effectively controlled. These findings suggest that rFVIIa is an effective and well-tolerated therapeutic option in the management of joint or muscle haemorrhage in patients with haemophilia and in patients with acquired inhibitors.

Identification of microdeletions spanning the Diamond-Blackfan anemia locus on 19q13 and evidence for genetic heterogeneity.

Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to approximately 1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.

An acquired inhibitor to factor X in a pediatric patient with extensive burns.

PURPOSE: An acquired inhibitor to factor X is an uncommon clinical finding in the pediatric population. We report the development of this type of inhibitor in a pediatric patient with extensive burns. PATIENTS AND METHODS: The patient's clinical course was complicated by persistent blood loss from the burn site. RESULTS: Characterization of the inhibitor demonstrated that it bound to the light chain of factor X. CONCLUSIONS: The inhibitor disappeared after treatment with i.v. immunoglobulin.

Practical guide to the diagnosis of thalassemia. Council of Regional Networks for Genetic Services (CORN).

Thalassemias occur in individuals of all ethnic backgrounds and are among the most common genetic diseases worldwide. The diagnosis of thalassemia can easily be part of primary medical practice. Here we outline a practical approach to the detection of thalassemias in three common clinical settings. The first involves any patient with a low mean corpuscular volume (MCV) with or without anemia. The second is a neonatal screening result indicating possible presence of thalassemia. Finally, evaluation for thalassemia should be considered in the context of family planning or pregnancy in patients whose ethnicity indicates origin from high risk geographic areas. We also review the various types of the thalassemia syndromes and provide an overview of general therapeutic considerations.

Newborn screening for sickle cell disease: 4 years of experience from California's newborn screening program.

PURPOSE: In this article we describe the success of a unique newborn screening program for sickle cell disease and other hemoglobinopathies. We will present and discuss 4 years of experience from the California Newborn Hemoglobinopathy Screening Program. METHODS: Several aspects that ensure the success of the program will be reviewed. These aspects include (a) the use of high-pressure liquid chromatography as the initial screening technique, (b) a confirmatory testing laboratory that incorporates DNA technology and innovative protein analysis using electrospray mass spectrometry, and (c) a complex follow-up strategy that employs regional nurses to track positive results and ensure timely enrollment of infants into treatment systems. RESULTS: Of these 2 million infants screened, 492 were diagnosed with some form of sickle cell disease; 290 (58.9%) were diagnosed with hemoglobin SS, 143 (29.0%) were diagnosed with hemoglobin SC, and 47 (9.5%) were diagnosed with S beta+thalassemia. CONCLUSION: The prevalence and ethnicity data presented here demonstrate the ineffectiveness of targeted screening and justify universal screening. Had targeted screening been performed in California during the past 4 years, 58 nonblack infants with sickle cell disease would have gone undiagnosed, and 6,921 nonblack infants with sickle cell trait would not have been identified.

Locus-Control-Region-Coupled Beta (S)(Antilles)- and Alpha(2)-Hemoglobin Genes Select for High Alpha(2)-Hemoglobin Expression in Adult Transgenic Mice.

Two transgenic lines of mice were produced which contained the beta(S)(Antilles)- and alpha(2)-hemoglobin genes tandemly coupled to the 'micro' locus control region (&mgr;LCR). The &mgr;LCRbeta(S)(Antilles)alpha(2)-hemoglobin transgenic mice expressed high levels of alpha(2)-hemoglobin while beta(S)(Antilles)-hemoglobin expression was virtually undetectable. Abundant alpha(2)-hemoglobin protein was observed in the blood of transgenic mice, while beta(S)(Antilles)-hemoglobin chains could not be detected. Transgenic red blood cells had substantially decreased sensitivity to osmotic lysis. Attempts to produce homozygotes containing the transgene were unsuccessful. The phenotype of these mice closely resembles that of beta-thalassemic mice. The &mgr;LCRbeta(S)(Antilles)alpha(2) transgenic mice demonstrate that if the &mgr;LCR is coupled to the beta(S)(Antilles)- and alpha(2)-hemoglobin genes in tandem, only the distal alpha(2)-hemoglobin gene is selected for expression to significant levels in adult mice. These results support a reciprocally competitive model for LCR-hemoglobin developmental switching. Copyright 1994 S. Karger AG, Basel

New advances in the pathophysiology and management of sickle cell disease.

The formation of the sickle cell hemoglobin polymer associated with deoxygenation of the sickle erythrocyte is a complex process. There are also many intracellular, extracellular, and erythrocyte membrane changes that are recognized to play important roles in the pathophysiology of this disease. The variability among these components accounts for the diversity observed in the phenotypic expression of sickle cell disease. This article reviews some of the recent developments in the understanding of the variables involved in the pathophysiology of sickle cell disease. Some of the new developments regarding clinical complications of sickle cell disease and their management are presented. New therapeutic options are reviewed. Finally, a discussion regarding transgenic models of sickle cell disease is presented.