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Biomedical subjects

Jeanne M Lusher

Publications and source records attributed to Jeanne M Lusher.

7 recordsLinked to original sources
PubMed2007

Pediatric reference values for molecular markers in hemostasis.

BACKGROUND: The hemostatic system is a developing and changing process relative to age. OBJECTIVES: To distinguish the differences in hemostatic parameters between children and adults, and to establish the normal range of these parameters in children of different age groups. DESIGN/METHODS: Blood was obtained from healthy children aged 1 to 18 years (n=70) and adults (n=26). Children were categorized into 3 age groups: 1 to 5 years, 6 to 10 years, and 11 to 18 years. Several coagulation and fibrinolysis parameters were determined. RESULTS: Children in all age groups showed no significant difference in mean levels of von Willebrand factor antigen and activity, activated partial thromboplastin time, fibrinogen, activated factor VII, tissue plasminogen activator, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor compared with adults. However, children aged 1 to 5 years had significantly higher mean values of soluble thrombomodulin (P=0.001), prothrombin time (P=0.03), tissue factor (P<0.001), thrombin-antithrombin complex (P<0.001), and D-dimer (P=0.009) whereas they had significantly lower mean levels of protein C activity (P=0.02) than did adults. CONCLUSIONS: These data indicate physiologic differences in the hemostatic system between children and adults and should serve as a useful reference guide in interpreting test results for children with suspected bleeding disorders.

Adolescent↗
PubMed2006

Milestones in hemophilia and concepts in future clinical trial design.

Hemophilia has long been documented as a bleeding disorder that afflicts males from early childhood. While some early societies set guidelines or laws to protect affected children, true advances in the understanding of the underlying deficiency and in the treatment of hemophilia have been relatively recent and continue today. This paper presents some of the key milestones that mark the path to current knowledge on hemophilia. Given that further studies are needed to explore issues such as optimal treatment and dosage, particularly in patients with inhibitors to factor VIII or factor IX, this paper also considers potential pitfalls in the design and conduct of clinical trials in hemophilia and suggests how careful forward planning may help to avoid them.

Blood Coagulation Factor Inhibitors↗
PubMed2005

Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation.

The safety and efficacy of a full-length sucrose-formulated recombinant factor VIII product (rFVIII-FS; Kogenate FS; Kogenate Bayer) was evaluated in previously untreated (PUPs) and minimally treated (MTP) patients with severe haemophilia A (FVIII <2%). Patients (37 PUPs; 24 MTPs) aged 0.1-25.7 months were treated with rFVIII-FS for a cumulative of 9,141 exposure days (EDs), median 114 EDs (range 4-478), on prophylactic or on-demand therapy. Eighty-nine percent of all treated bleeding episodes were successfully treated with 1 (74%) or 2 (15%) infusions. Clinical response to first infusion for each bleeding episode was rated as 'excellent' in 58%, or 'good' in 33%, of all cases. Recombinant FVIII-FS was used in 27 surgical procedures, mainly catheter implantations, which were all conducted without bleeding complications. FVIII recovery mean values (approximately 2%/kg/IU) were as expected for any licensed FVIII concentrate. FVIII neutralizing antibody formation was 15% (9/60). Aside from inhibitor formation, three adverse events were rated as 'at least possibly drug-related' for a total drug-related adverse event rate of 0.14%. No viral seroconversions were observed. Overall, excellent safety and efficacy were demonstrated with rFVIII-FS for therapy of young children with severe haemophilia A.

Antibody Formation↗
PubMed2004

The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B.

This international clinical trial evaluated the safety and efficacy of recombinant factor IX (rFIX) in previously untreated patients (PUPs) with severe or moderately severe hemophilia B (FIX activity, < or = 3 IU/dL). Sixty-three PUPs aged younger than 1 month to 14 years received rFIX (median treatment duration, 37 months; range, 4-64 months). Mean rFIX recovery (0.68 +/- 0.27 IU/dL per IU/kg) remained constant over 5 years and was similar in infants (1 month to < 2 years) and children (2 to < 12 years). Fifty-four PUPs used rFIX (median dose, 62.7 IU/kg per infusion; range, 8.2-292 IU/kg) to treat 997 hemorrhages. Bleeding was well controlled, with 75% of hemorrhages requiring only one rFIX infusion. Response to rFIX was "excellent" or "good" in 94% of cases. Effective hemostasis was achieved in 32 PUPs receiving rFIX for routine prophylaxis, with 91% of prophylaxis responses rated "excellent." rFIX administered for 30 surgical procedures in 23 PUPs achieved hemostasis for all rated procedures. Five patients experienced allergic-type manifestations, including 2 (3%) patients who developed FIX inhibitors (both > 5 BU/dL). rFIX was well tolerated, with no associated thrombotic events or evidence of viral transmission. These data indicate that rFIX is a safe and effective treatment for PUPs with hemophilia B.

Adolescent↗
PubMed2003

Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.

In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain-deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P <.02) and area under the curve (AUC, P <.04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.

Adolescent↗
PubMed2002

First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development.

The first of the prospective multicenter studies in previously untreated patients (PUPs) with a recombinant factor VIII (FVIII) concentrate began in January 1989. Over the past 11 years, PUP studies have amassed a great deal of information concerning safety, efficacy, and inhibitor development of the two "first-generation" recombinant (r) FVIII concentrates (Kogenate and Recombinate) and of two "second-generation" products (ReFacto and Kogenate FS, which is formulated with sucrose rather than with albumin). Each of these products has proved to be safe, effective, and well-tolerated. Side effects have been rare and mild in nature. There have been no clinical reactions to hamster or murine proteins. During the course of the multinational PUP trials with Kogenate, Recombinate, and ReFacto, inhibitors developed in 29.7, 31, and 33%, respectively, of severely affected PUPs. Half of these were high titer and half were low titer. In each of these trials, several inhibitors were transient. PUPs and minimally treated patients (MTPs) in the Kogenate SF trial have not been followed long enough to determine the incidence of inhibitor development; however, the product appears to be safe and effective. Following demonstration of safety and efficacy with each rFVIII concentrate in previously treated patients with hemophilia A, studies in PUPs began. In general, the prospective trials in PUPs with each recombinant product were conducted similarly, allowing comparison of data. This article is intended to provide a review of the experience with both first- and second-generation rFVIII products in the prospective clinical trials in PUPs.

Antibody Formation↗