Extreme Reticulocytosis After Splenectomy in a Patient With Hemoglobin Mizuho.

BACKGROUND: Patients with Hb Mizuho may be splenectomized at a young age to decrease their need for blood transfusions. OBSERVATIONS: Transfusion-dependency decreased dramatically in a 4-year-old white boy with Hb Mizuho after splenectomy. Surprisingly, he developed reticulocytosis (>1000×10 9 /L) with a peak reticulocyte percentage of 49%, and erythrocyte abnormalities, including Heinz bodies, Howell-Jolly bodies, and basophilic stippling. Manual reticulocyte counting and flow cytometric measurement with anti-CD71 antibodies supported a truly elevated reticulocyte count. CONCLUSIONS: We propose possible explanations for the extreme reticulocytosis that arose postsplenectomy and compare the reticulocyte count in the present case with previously published cases.

Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER).

Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received fresh frozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤ 2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 µg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency.

Replacement therapy for bleeding episodes in factor VII deficiency. A prospective evaluation.

Patients with inherited factor VII (FVII) deficiency display different clinical phenotypes requiring ad hoc management. This study evaluated treatments for spontaneous and traumatic bleeding using data from the Seven Treatment Evaluation Registry (STER). One-hundred one bleeds were analysed in 75 patients (41 females; FVII coagulant activity <1-20%). Bleeds were grouped as haemarthroses (n=30), muscle/subcutaneous haematomas (n=16), epistaxis (n=12), gum bleeding (n=13), menorrhagia (n=16), central nervous system (CNS; n=9), gastrointestinal (GI; n=2) and other (n=3). Of 93 evaluable episodes, 76 were treated with recombinant, activated FVII (rFVIIa), eight with fresh frozen plasma (FFP), seven with plasma-derived FVII (pdFVII) and two with prothrombin-complex concentrates. One-day replacement therapy resulted in very favourable outcomes in haemarthroses, and was successful in muscle/subcutaneous haematomas, epistaxis and gum bleeding. For menorrhagia, single- or multiple-dose schedules led to favourable outcomes. No thrombosis occurred; two inhibitors were detected in two repeatedly treated patients (one post-rFVIIa, one post-pdFVII). In FVII deficiency, most bleeds were successfully treated with single 'intermediate' doses (median 60 µg/kg) of rFVIIa. For the most severe bleeds (CNS, GI) short- or long-term prophylaxis may be optimal.

Effect of X-ray radiation exposure on lyophilized recombinant activated factor VII (formulated for storage at room temperature).

OBJECTIVE: To investigate effects of air transport and X-ray radiation exposure through airport security of a new room temperature-stable rFVIIa formulation (NovoSeven/NovoSeven RT, Novo Nordisk A/S, Bagsvaerd, Denmark) lyophilized using in vitro study methodology, thus evaluating possible effects of exposure through airport security and airplane travel. RESEARCH DESIGN AND METHODS: The effect of X-ray radiation exposure of rFVIIa and the solvent histidine at two different doses (400 microSv and 2000 microSv) was examined immediately after exposure, and post-exposure after storage at 30 degrees C for 1 month. References samples, not exposed to X-ray radiation, were used for comparison. MAIN OUTCOME MEASURE: Stability of rFVIIa after X-ray radiation exposure. RESULTS: All product parameters analyzed were within the acceptance criteria as well as within shelf life specification limits for the selected parameters for each product. CONCLUSION: The product rFVIIa and solvent histidine are therefore not expected to be affected as a consequence of airplane traveling and X-ray exposure during airport security check using hand luggage scanners.

Challenges of defining reliable clinical surrogate end points in haemophilia trials: a critical review.

The success of a treatment in haemophilia patients experiencing a bleeding episode is very difficult to define. A variety of efficacy assessment tools have been developed in an effort to better assess when haemostasis has been achieved. These assessment tools are particularly important for the evaluation of the efficacy of therapeutic agents whose mechanism of action is based on pharmacological activity in haemostasis rather than upon the principle of 'replacement therapy'. This review focuses on a number of efficacy measures, summarizing their methodology and discussing their validity. In addition, future developments and requirements in order to evaluate the effectiveness of haemostatic treatment are discussed. The majority of end points used for evaluation of haemostasis relate to the relief of symptoms arising from bleeds. The results of this review highlight that several efficacy end points are frequently combined in order to provide a more comprehensive assessment of efficacy. Key limitations of current methodology are the subjectivity of assessment by either the patient or clinician, and the incomparability of results between trials.

In vitro stability of lyophilized and reconstituted recombinant activated factor VII formulated for storage at room temperature.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is indicated to treat bleeding episodes or prevent bleeding related to surgery in patients with hemophilia A or B who have antibodies to coagulation factors VIII or IX. The first-generation rFVIIa formulation is stable when stored under refrigeration. A new formulation has been developed for storage at room temperature, which may improve patients' access to treatment during bleeding episodes. OBJECTIVE: These in vitro experiments were conducted to evaluate the stability of the new formulation of rFVIIa, both lyophilized and reconstituted, under the expected storage conditions, as well as at higher temperatures. METHODS: The stability of the new rFVIIa formulation when stored under various conditions before and after reconstitution was evaluated in terms of retained activity (clotting assay), rFVIIa content (high-performance liquid chromatography [HPLC]), and rFVIIa degradation products (HPLC), including aggregates (dimer/oligomer). Activity was analyzed within specific limits representing the allowable minimum/maximum for each test parameter at the end of the product's shelf-life, as adopted by the European Medicines Agency and the US Food and Drug Administration. Before reconstitution, vials from 9 lots of the new rFVIIa formulation, 3 of each size (1, 2, and 5 mg/vial), were stored at refrigerated temperature (5 degrees C) and at room temperature (25 degrees C) for 24 months, and at 30 degrees C for 12 months. To simulate short-term exposure to temperatures higher than recommended, samples were stored at 40 degrees C for 6 months, followed by storage at 25 degrees C for 12 months. To simulate the home setting, in which the product may be alternately stored in and out of the refrigerator, samples were stored at 30 degrees C for 8 hours and then at 5 degrees C for 16 hours, repeated daily for 5 days. To analyze the effect of storage at extremely elevated temperatures, samples were exposed to temperatures of 50 degrees C, 60 degrees C, and 70 degrees C for 12 hours. After reconstitution, samples were maintained at 25 degrees C for up to 6 hours or at 5 degrees C for up to 24 hours. RESULTS: The specific activity and rFVIIa content of the new lyophilized formulation remained stable after storage for 24 months at 5 degrees C and 25 degrees C, and for 12 months at 30 degrees C; after 5 days of daily alternation between storage at 5 degrees C and 30 degrees C; and after storage for 6 months at 40 degrees C followed by 12 months at 25 degrees C. When stored at 50 degrees C and 60 degrees C for 12 hours, activity remained constant, whereas rFVIIa aggregates increased within the specified limits; after storage at 70 degrees C for 12 hours, rFVIIa activity decreased in parallel with the formation of aggregates, which exceeded the specified limit for the 5-mg product. After reconstitution, samples of all vial sizes of the new rFVIIa formulation retained their activity when stored at 25 degrees C for 6 hours and at 5 degrees C for 24 hours. CONCLUSIONS: In these in vitro experiments, the new lyophilized formulation of rFVIIa was stable when stored for 24 months at 25 degrees C, 12 months at 30 degrees C, 6 months at 40 degrees C, and 12 hours at 50 degrees C and 60 degrees C without compromise to its activity or rFVIIa content. The reconstituted product retained activity when stored at 25 degrees C for 6 hours and at 5 degrees C for 24 hours.

In vitro stability of two formulations of recombinant activated factor VIIa reconstituted in inappropriate solvents or at inappropriate volumes.

BACKGROUND: Recombinant activated factor VIIa (rFVIIa) is indicated for on-demand treatment of bleeding and the prevention and treatment of surgical bleeding in patients with hemophilia A or B who have antibodies to coagulation factors VIII or IX. The currently approved single-use formulation of rFVIIa is freeze dried and is stable for up to 3 years when stored at 2 degrees C to 8 degrees C (36 degrees F-46 degrees F). A new formulation has been developed that is stable for up to 2 years when stored at temperatures up to 25 degrees C (77 degrees F). This formulation does not require refrigerated storage and does not have to be brought to room temperature before use. Both formulations must be reconstituted before use. The original formulation is reconstituted with sterile water for injection (SWFI), whereas the new formulation is reconstituted with a solvent containing histidine. OBJECTIVE: This study examined the stability of the 2 formulations of rFVIIa after being dissolved in inappropriate types or volumes of solvent. Although the new formulation is expected to take the place of the original formulation, inappropriate reconstitution may accidentally occur in the transition period during which both products are available. METHODS: A series of in vitro experiments was designed to determine the chemical and physical stability of the 2 formulations under 4 sets of conditions. In part 1, the new formulation was reconstituted with appropriate volumes of inappropriate solvent (SWFI or physiologic saline) and in the appropriate histidine solvent. In part 2, the new formulation was reconstituted in inappropriate volumes of saline, histidine solvent, or a mixture of saline and histidine solvent. In part 3, the original formulation was reconstituted with histidine solvent. In part 4, the new formulation was mixed with the original formulation, each correctly reconstituted but subsequently pooled. RESULTS: The active substance, rFVIIa, remained chemically and physically stable for up to 6 hours of storage at 25 degrees C (77 degrees F) or for up to 24 hours of storage at 5 degrees C (41 degrees F) in the experiments in which an inappropriate type or volume of solvent was used. However, the concentration of rFVIIa stated in the product labeling was not achieved when the product was reconstituted in the incorrect volume of solvent. No changes in rFVIIa concentration, rFVIIa aggregates (dimers, oligomers, or polymers), degradation products, oxidized forms, coagulation activity, clarity, or pH were seen after storage of the reconstituted products. CONCLUSION: Based on the results of these experiments, the 2 rFVIIa products should be reconstituted using the appropriate solvent at the correct volume.

Evidence-based use of recombinant FVIIa (NovoSeven, NiaStase) for the treatment of hemophilia with inhibitors in children and adolescents.

Children and adolescents comprise a significant proportion of the hemophilia population, including those patients who have developed inhibitors to factor VIII or FIX. We examine the use of rFVIIa for the treatment of bleeding episodes and the prevention of bleeding in children and adolescents with hemophilia A and B with inhibitors, focusing on registry data and recent clinical trial results. Based on this review of the literature, we conclude that recombinant FVIIa is safe and effective for use in controlling bleeding in these patient populations.