1Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.
2Department of Pediatrics, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea.
3Department of Pediatrics, Incheon Medical Center Beakryung Hospital, Incheon, Korea.
4Division of Pediatric Hematology/Oncology, Asan Medical Center Children's Hospital, Department of Pediatrics, University of Ulsan College of Medicine, Seoul, Korea.
5Green Cross Laboratories, Yongin, Korea.
6Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
Continuous infusion of factor VIII (FVIII) is a more cost-effective method for treating hemophilia A than intermittent bolus injection. However, there is currently no specific data in Korea about the progress of
Three commercial FVIII concentrate products (two recombinant FVIII and one plasma-derived) were used.
For the three drugs, in vitro FVIII:C decreased over the 8 hours following reconstitution (
In vitro FVIII:C decreased after reconstitution, but activity was maintained at over 90% of the baseline value during 8 hours. Exposure to indoor light did not accelerate the loss of FVIII:C over the experimental time. This result indicates that CI with FVIII is available in 8-hour intervals, with no indoor light-exposure precautions needed.
In the management of patients with hemophilia A, continuous infusion (CI) of factor VIII (FVIII) is a more cost-effective method than bolus injection (BI), because it prevents unnecessary high peak of FVIII coagulant activity (FVIII:C), to maintain the desired level of FVIII from a pharmacological perspective [1, 2]. In practice, the benefits of using CI of FVIII was confirmed compared to BI, especially in cases of major surgery in patients with hemophilia A.
The nadir level of FVIII in the CI group was higher than that in the BI group [3, 4], and dangerous drops of FVIII levels below 0.3% were more frequent in patients receiving BI than those receiving CI . Hemoglobin levels were also higher with CI than with BI, and the BI group required more blood transfusions than the CI group . Major bleeding complications developed only in the BI group . The CI group required 30-36% lower doses of FVIII than did the patients receiving BI [3, 5]. Although some reports have raised concerns about the possibility of inhibitor development, recent large-scale studies have shown no increased rate of inhibitor development in CI [6, 7]. Despite the aforementioned advantages of CI, there is currently no specific guideline for how frequently a FVIII product should be changed over the course of one day, or of the indoor light-shielding requirements for FVIII-containing vessels or syringes in Korea.
Acquiring absolute hemostasis in patients with hemophilia A depends on maintaining the desired FVIII:C level. There are two crucial factors for determining FVIII:C - individual
Three commercial FVIII products were used in this study for
Drug A (500 IU per vial) was reconstituted in 4 mL of sterile distilled water, according to manufacturer's instructions. After 30 minutes of stabilizing, 4 mL of the drug A diluent was further diluted 100-fold in sterile distilled water. Drug B (250 IU per vial) was diluted in 5 mL of sterile distilled water, according to the manufacturer's guidelines, allowing 30 minutes for reconstitution. Drug B was then further diluted 80-fold in sterile distilled water. Drug C (250 IU per vial) was diluted in 10 mL of sterile distilled water, based on the manufacturer's instructions. After 30 minutes, drug C was further diluted 20-fold in sterile distilled water. Each solution of drug A, B, and C was divided into 50 polyethylene tubes, each containing 1 mL of fluid. These were then divided into two groups: indoor light-exposed and light-shielded. The general outline for preparing the experiment is shown in Fig. 1.
To analyze the changes of
There was no statistical difference between FVIII:C in the indoor light-exposed and light-shielded groups for all three drugs (
Generally, infusion of FVIII concentrate according to the body weight (IU/kg) is known to raise the patient's FVIII:C by approximately 2 IU/dL. However, the drug should be supplemented according to the patient's response, due to considerable inter- and intra-patient variability in pharmacokinetics (PK) [8, 9]. There has been an emphasis on individual dosing of clotting factors using PK, to avoid the inadequate management and under-treatment of patients who require additional dosage, and to prevent potential overtreatment of the patients who require lower doses, which results in wasting of an expensive product [8, 9]. It is possible to calculate the velocity of CI if we obtain the level of FVIII from patients with hemophilia A during treatment [8, 9].
Several factors influence individual PK in the use of FVIII for treating patients with hemophilia A without inhibitor formation - product type, the patient's age, weight, body surface area, plasma volume, endogenous von Willebrand factor level, blood type, and hematocrit [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]. Thus, the indicators of PK change with advanced age, and may vary depending on the circumstances of each hemophilia patient. Besides the aforementioned factors, the
Several studies have reported the
In this study, the decline of
In comparison to the results of previous reports [21, 22, 23, 24, 25], the level of
In a previous report, the activity of reconstituted FVIII was diminished to approximately 30% of its baseline activity after 10 hours of daylight exposure, while shielding in foil wrap prevented the harmful effects of daylight . However, persistent exposure to natural daylight is very rare in a practical clinical environment, especially for patients with hemophilia A who are under CI of FVIII, which is why indoor light was used in this study. There was no difference between FVIII:C in the indoor light-exposed or light-shielded groups during the experimental time frame of 8 hours. This result shows that CI using FVIII concentrate over a period of 8 hours does not require additional protection from indoor light in hospital rooms.
The general outline of the experimental procedure is shown. Estimation of in vitro FVIII:Ca) was performed using three commercial products, divided into indoor light-exposed and light-shielded experimental groups. a)Factor VIII coagulant activity.