A 6‐year follow‐up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia

Abstract

The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmo haemophilia treatment centre during a 6-year period. A retrospective survey of medical records for the years 1997-2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and 'other bleeds') was compiled. The patients were stratified by age (0-6, 7-12, 13-18, 19-36 and >36 years) and joint score (0, 1-6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty-one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient-years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high-dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re-assessment and individual dose tailoring.

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

“…Population PK analyses resolve the observed variability into its interpatient and random assay within patient error components, but whereas these methods [13] have a long history of usage for the more common blood-clotting drugs, that is not the case with haemophilia treatments. Only recently a population analysis has been reported for factor VIII dose individualisation in healthy adults with haemophilia A before surgery [12,14]. However, PK − and particularly population models − can address several of the above problems with factor VIII:C treatment.…”

“…However, the NCA has less utility as a predictive tool, and its use compared with the advantages offered by compartmental PK is criticized [9][10][11]. Several studies have addressed the compartmental PK properties of factor VIII [12]. Such PK models address the underlying process of absorption, distribution, and elimination as model parameters, allowing for a better prediction.…”

Nacionalna priporočila za obravnavo bolnikov s hemofilijo

“…S tem se oseba s težko stopnjo hemofilije nahaja v območju srednje stopnje, pri kateri praviloma ni t. i. spontanih krvavitev. Posamezni bolniki kljub najnižji aktivnosti FVIII / IX > 3 % zakrvavijo, drugi pa kljub aktivnosti, nižji od 1 %, ne zakrvavijo (28). Ta dejstva je treba upoštevati pri določanju pogostnosti vbrizgavanja in odmerka.…”

Response to Gringeri et al.: ‘recombinant full‐length factor VIII (FVIII) and extended half‐life FVIII products in prophylaxis – new insight provided by pharmacokinetic modelling’

“…Correlations between trough level and the risk of bleeding have been shown, particularly for troughs <1 IU dL À1 [10,11], and trough levels >3 IU dL À1 may be desired in clinical practice in specific circumstances. Yet some patients with trough levels <1 IU dL À1 may not bleed at all [10], and as the authors themselves remark, there is probably no one-size-fits-all trough level for optimal prophylaxis.…”

“…Correlations between trough level and the risk of bleeding have been shown, particularly for troughs <1 IU dL À1 [10,11], and trough levels >3 IU dL À1 may be desired in clinical practice in specific circumstances. Yet some patients with trough levels <1 IU dL À1 may not bleed at all [10], and as the authors themselves remark, there is probably no one-size-fits-all trough level for optimal prophylaxis. In clinical practice, many aspects, including a patient's individual bleeding phenotype, activity level, lifestyle, presence of prior joint damage and ability and/or willingness to comply with the demands of the treatment regimen, contribute to the success of treatment and should be taken into consideration, rather than relying solely on PK or an arbitrary FVIII trough level.…”