| 1. |
- Astermark, Jan
(author)
-
Inhibitor development: patient-determined risk factors.
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 66-70
-
Journal article (peer-reviewed)abstract
- Summary. The reasons that inhibitory factor VIII antibodies develop in only a fraction of patients with haemophilia A remain unclear, but studies of genetically related subjects have indicated that the immunological outcome of replacement therapy is to a large extent determined by patient-related risk factors. Non-genetic factors will also influence the inhibitor risk, since events challenging the immune system will elicit and stimulate immune regulatory processes with the potential of modifying the immune response. Further insight into the immunological pathways and risk factors involved will be important in order to better predict and prevent this complication. This review will briefly summarize the data obtained to date in unrelated and related subjects in the Malmö International Brother Study (MIBS) regarding genetic factors and discuss how these factors might interact with non-genetically determined factors and events.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- McCraw, A., et al.
(author)
-
Considerations in the laboratory assessment of haemostasis
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16:s5, s. 74-78
-
Research review (peer-reviewed)abstract
- This review outlines a number of key issues when performing laboratory testing of homeostasis. The effect pre-analytical variables have on the reliability and consistency of screening tests is often forgotten due to a lack of understanding and awareness. This can be improved through educating healthcare professionals who are involved in taking blood for assessment. Recent advances in coagulation testing have not enabled laboratories to replace the Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) screening tests with more advanced assays and they continue to play an important role with the advantage of being easily automated. However, there are many analysers on the market, each with varying sensitivity to coagulation defects and it is important to keep this in mind when interpreting results.
|
|
| 5. |
|
|
| 6. |
- Astermark, Jan, et al.
(author)
-
Clinical issues in inhibitors
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 54-60
-
Research review (peer-reviewed)abstract
- Anamestic inhibitors represent the major complication of haemophilia therapy now that clotting factor concentrates are virtually free of pathogen-transmission risk. Conventional clotting factor replacement is usually insufficient to prevent or treat bleeding in a haemophilia patient with a high responding inhibitor so that alternative treatment with bypassing agents is required. Despite their relative efficacy, their use does not achieve the same invariable haemostasis that patients without inhibitors do following treatment with factor concentrate replacement. This has led to the attempt to eradicate such inhibitors with immune tolerance induction. Success is not invariable, however, and many patients with long-term persistent high-titre inhibitors continue to experience great morbidity. Recently, this has given rise on a limited basis to attempts to use bypassing agents in prophylaxis regimens in an effort to alleviate this extreme morbidity. Each of these strategies is discussed in the context of their relative benefits and risks.
|
|
| 7. |
- Berntorp, Erik, et al.
(author)
-
The role of prophylaxis in bleeding disorders
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16:s5, s. 189-193
-
Research review (peer-reviewed)abstract
- The rationale for long-term prophylaxis in more severe forms of von Willebrand's disease (VWD) is obvious, as mucosal bleeding and haemophilia-like joint bleeds resulting in chronic morbidity may occur. However, the experience with prophylactic treatment in this group is scanty. An international VWD Prophylaxis Network (VWD PN) was established in 2006. The VWD PN will investigate prophylaxis with retrospective and prospective studies. Eighteen centres in Europe and North America are recruiting patients and an additional 40 centres are preparing for or evaluating participation. In the absence of randomized prospective studies for most rare bleeding disorders, guidelines for prophylaxis are a subject of controversy. In situations where there is a strong family history of bleeding, long-term prophylaxis is administered in selected cases. Short intervals of prophylaxis can also be given before some surgeries or during pregnancy. The benefits of prophylaxis must be balanced by the risk of side effects. Therefore, it is essential to delineate its management in a specialized comprehensive care environment. In haemophilia, decades of clinical experience and numerous retrospective and, recently, prospective studies clearly demonstrate that prophylactic treatment is superior to on-demand treatment, regardless of whether the outcome is the number of joint- or life-threatening bleeds, arthropathy evaluated by X-ray or MRI, or quality of life measured by generic or haemophilia-specific instruments. Optimal prophylactic treatment should be started early in life (primary prophylaxis) but various options exist for the dose and dose interval. These depend on the objective of treatment in the individual patient, which, in turn, is dependent on resources in the health care system.
|
|
| 8. |
- Berntorp, Erik, et al.
(author)
-
Treatment of haemophilia A and B and von Willebrand's disease : summary and conclusions of a systematic review as part of a Swedish health-technology assessment
- 2012
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 18:2, s. 158-165
-
Research review (peer-reviewed)abstract
- In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandvårds-och läkemedelsförmånsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvärdering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important.
|
|
| 9. |
- Brodin, Elisabeth, et al.
(author)
-
The Swedish version of the Haemophilia Activity List.
- 2011
-
In: Haemophilia : the official journal of the World Federation of Hemophilia. - : Wiley. - 1365-2516. ; 17:4, s. 662-8
-
Journal article (peer-reviewed)abstract
- There has been increasing interest in the patient's perspective on outcome of treatment. The Haemophilia Activity List (HAL) has been developed as a disease-specific questionnaire for haemophilia patients and is a validated self-report measure of function developed according to WHO's International Classification of Functioning, Disability and Health. To validate HAL in Sweden. The Dutch and English versions of HAL were translated into Swedish using 'the forward-backward translation' method and merged into a final Swedish version. Validation was performed against the Swedish version of the questionnaires Arthritis Impact Measurement 2 (AIMS 2) and Impact on Participation and Autonomy (IPA). Two hundred and twenty-five patients with severe and moderate forms of haemophilia A and B from three centres were invited to participate in the study. Spearman's rank correlation test was used for validation, and internal consistency of the HAL was calculated with Cronbach's alpha. Eighty-four patients (39%) (18-80 years old) filled out the questionnaires. The internal consistency of the Swedish version of HAL was high, with Cronbach's alpha being 0.98-0.71. Function of the legs had the highest consistency and transportation had the lowest. The correlation was excellent between the HAL sum score and AIMS 2 physical (r = 0.84, P< 0.01), IPA autonomy indoors (r = 0.83, P < 0.01) and autonomy outdoors (r = 0.89, P < 0.01). The Swedish version of HAL has both internal consistency and convergent validity and may complement other functional tests to gather information on the patient's self-perceived ability.
|
|
| 10. |
- Halldén, Christer, 1957-, et al.
(author)
-
Investigation of disease-associated factors in haemophilia A patients without detectable mutations
- 2012
-
In: Haemophilia. - : Blackwell. - 1351-8216 .- 1365-2516. ; 18:3, s. e132-e137
-
Journal article (peer-reviewed)abstract
- To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.
|
|
| 11. |
- Halldén, Christer, et al.
(author)
-
Investigation of disease-associated factors in haemophilia A patients without detectable mutations
- 2012
-
In: Haemophilia. - : Wiley-Blackwell Publishing Ltd. - 1351-8216 .- 1365-2516. ; 18:3, s. e132-e137
-
Journal article (peer-reviewed)abstract
- To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiencyrespectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.
|
|
| 12. |
|
|
| 13. |
- Khawaji, Mohammed, et al.
(author)
-
Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term prophylaxis.
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 495-501
-
Journal article (peer-reviewed)abstract
- Summary. Physical activity has been considered as an important factor for bone density and as a factor facilitating prevention of osteoporosis. Bone density has been reported to be reduced in haemophilia. To examine the relation between different aspects of physical activity and bone mineral density (BMD) in patients with severe haemophilia on long-term prophylaxis. The study group consisted of 38 patients with severe haemophilia (mean age 30.5 years). All patients received long-term prophylaxis to prevent bleeding. The bone density (BMD g cm(-2)) of the total body, lumbar spine, total hip, femoral neck and trochanter was measured by dual energy X-ray absorptiometry. Physical activity was assessed using the self-report Modifiable Activity Questionnaire, an instrument which collects information about leisure and occupational activities for the prior 12 months. There was only significant correlation between duration and intensity of vigorous physical activity and bone density at lumber spine L1-L4; for duration (r = 0.429 and P = 0.020) and for intensity (r = 0.430 and P = 0.019); whereas no significant correlation between all aspects of physical activity and bone density at any other measured sites. With adequate long-term prophylaxis, adult patients with haemophilia are maintaining bone mass, whereas the level of physical activity in terms of intensity and duration play a minor role. These results may support the proposition that the responsiveness to mechanical strain is probably more important for bone mass development in children and during adolescence than in adults and underscores the importance of early onset prophylaxis.
|
|
| 14. |
- Klintman, Jenny, et al.
(author)
-
Thrombin generation in vitro in the presence of by-passing agents in siblings with severe haemophilia A.
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 210-215
-
Journal article (peer-reviewed)abstract
- Summary. Previous data have shown an inter-individual difference in the thrombin generating capacity in vitro as well as phenotypic bleeding pattern among patients with severe haemophilia A (FVIII:C activity below 1%). The reason for this is not known. In addition, there are no reports on how thrombin generation may correlate between siblings. In this study, we evaluated and compared thrombin generation in vitro using plasma samples in the presence of by-passing agents (FEIBA((R)) and NovoSeven((R))) in 21 unrelated brother pairs with and without inhibitors enrolled in the Malmö International Brother Study (MIBS). Mean maximum thrombin formation in patients with a current inhibitor titer was 182.0 +/- 52.8 mmol mL(-1) (FEIBA((R))) and 130.7 +/- 54.9 mmol mL(-1) (rFVIIa), respectively, and somewhat higher in those without inhibitors, 222.7 +/-85.5 mmol mL(-1) (FEIBA((R))) and 142.8 +/-53.6mmol mL(-1) (rFVIIa) (P = 0.16 and 0.29). The variance regarding the maximum thrombin production within a family was significantly lower compared with the thrombin production between families (P < 0.001 for both FEIBA((R)) and NovoSeven((R))). Our data indicate that genetically determined factors, other than the FVIII:C activity seems to influence the phenotypic variation in thrombin formation in the presence of by-passing agents. The nature of these determinants remains to be identified.
|
|
| 15. |
- Lindvall, Karin, et al.
(author)
-
Daily dosing prophylaxis for haemophilia : A randomized crossover pilot study evaluating feasibility and efficacy
- 2012
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 18:6, s. 855-859
-
Journal article (peer-reviewed)abstract
- Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12 + 12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.
|
|
| 16. |
- Lindvall, Karin, et al.
(author)
-
Knowledge of disease and adherence in adult patients with haemophilia.
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 592-596
-
Journal article (peer-reviewed)abstract
- Summary. Patients with moderate and severe haemophilia are evaluated on a regular basis at their haemophilia centres but patients with mild haemophilia are seen less often because of fewer problems related to their disease. The needs of patients with milder forms of haemophilia, however, are often underestimated, both by the patient and staff at healthcare facilities. This study evaluated the knowledge of disease and adherence to treatment among patients with severe, moderate and mild haemophilia. This was a prospective multicentre study performed in Haemophilia Centres in Scandinavia. A total of 413 (67%) of 612 patients aged >25 years with mild, moderate and severe haemophilia completed a self-administered questionnaire. The mean age of the respondents was 49.7 years (range 25-87 years). Of the 413 respondents, 150 had a mild, 86 had a moderate and 177 had a severe form of haemophilia. A total of 22 (5%) patients did not know the severity of their disease, and 230 (56%) patients knew the effect of factor concentrate in the blood. Of the 413 respondents, 53 (13%) of the cohort never treated a haemorrhage. Patients with mild haemophilia, P
|
|
| 17. |
- Ljung, Rolf
(author)
-
The optimal mode of delivery for the haemophilia carrier expecting an affected infant is vaginal delivery.
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 415-419
-
Journal article (peer-reviewed)abstract
- Summary. The optimal mode of delivery of a haemophilia carrier expecting a child is still a matter of uncertainty and debate. The aim of this commentary/review is to suggest that normal vaginal delivery should be the recommended mode of delivery for the majority of carriers, based on review of studies on obstetric aspects of haemophilia. About 2.0-4.0% of all haemophilia boys born in countries with a good standard of health care will suffer from ICH during the neonatal period. This is an average figure including all modes of delivery and regardless of whether the carrier status of the mother or the haemophilia status of the foetus was known or not at the time of delivery. On the basis of current literature, one may conclude that the risk of serious bleeding in the neonate affected with haemophilia is small in conjunction with normal vaginal delivery. It should be possible to further reduce the low frequency of complications if appropriate precautions are taken when planning the delivery in pregnant woman with known carrier status, if the sex of the foetus is known and, even more, when the haemophilia status of the foetus is known. Instrumental delivery such as use of vacuum extraction and foetal scalp monitors must be avoided at delivery of carriers.
|
|
| 18. |
- Perry, D., et al.
(author)
-
FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16:1, s. 80-89
-
Journal article (peer-reviewed)abstract
- In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria.
|
|
| 19. |
- Salek, S. Z., et al.
(author)
-
The need for speed in the management of haemophilia patients with inhibitors
- 2011
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 17:1, s. 95-102
-
Journal article (peer-reviewed)abstract
- Rapid control of bleeding is the key to reducing bleeding complications and thereby preserving joint and musculoskeletal function in haemophilia patients with inhibitors. However, this requires early diagnosis following the onset of bleeding and strategies for rapid treatment in an outpatient setting. Overarching themes on the need for speed in managing bleeds in haemophilia patients were examined by a panel of clinicians experienced in managing inhibitor patients and joint disease during the Third Zurich Haemophilia Forum on 8 May 2009. This report summarizes the opinions of the panel on how to achieve rapid bleeding control in inhibitor patients and areas that were identified by the panel for future research or as needing new consensus guidelines. The consensus was that home treatment should be established for haemophilia patients with inhibitors, as it is associated with a faster time to treatment, as well as improvements in the quality of life of patients and their carers. In addition, as improved haemostatic control now allows inhibitor patients to participate in a wider range of physical activities, specific guidelines are required on which types of sport and work are appropriate. It was agreed that clear, systematic approaches are needed for early diagnosis of joint and muscle bleeds in inhibitor patients, which could facilitate rapid treatment. There may be opportunities for exploiting new diagnostic techniques from osteoarthritis to enable earlier diagnosis of haemophilic arthropathy. Overall, it was concluded that greater emphasis should be placed on education and patients' psychological needs, to enable inhibitor patients to cope up more effectively with their disease.
|
|
| 20. |
- Blomback, M, et al.
(author)
-
von Willebrand disease biology
- 2012
-
In: Haemophilia : the official journal of the World Federation of Hemophilia. - : Wiley. - 1365-2516. ; 1818 Suppl 4, s. 141-147
-
Journal article (peer-reviewed)
|
|
| 21. |
- Collins, P. W., et al.
(author)
-
Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia
- 2011
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 17:1, s. 2-10
-
Research review (peer-reviewed)abstract
- The pharmacokinetic (PK) response to factor VIII (FVIII) and factor IX varies between patients and this has important clinical implications for treatment. Although PK is affected by patient characteristics, this relationship is too weak to infer a result for an individual and, if required, PK must be measured. An important determinant of the efficacy of prophylaxis is the length of time an individual spends with a low level of coagulation factor. This time is more dependent on the patient's coagulation factor half-life and the frequency of dosing than in vivo recovery and dose infused. Improved understanding of the effect of PK and dose frequency on factor levels in patients on prophylaxis will help tailor regimens to individuals better and allow more cost effective use of coagulation factor concentrates. Calculations suggest that adults need less FVIII per kg body weight than children. The effect of half-life on trough levels questions the logic of Monday, Wednesday, Friday dosing and suggests a role for innovative regimens including low-dose daily treatment which leads to either higher trough levels or decreased FVIII requirement. This may expand access to prophylaxis in healthcare systems with limited resources and potentially improve patient outcomes. The ideal trough level will vary between individuals and at different times of their lives and may be <1 IU dL(-1). If PK is to be used in routine clinical practice, a simplified method for its measurement is required and this methodology is becoming available.
|
|
| 22. |
- Björkman, Sven
(author)
-
A commentary on the differences in pharmacokinetics between recombinant and plasma-derived factor IX and their implications for dosing
- 2011
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 17:2, s. 179-184
-
Journal article (other academic/artistic)abstract
- This commentary aims to summarize all aspects of the difference in pharmacokinetics (PK) between recombinant factor IX (rFIX) and plasma-derived factor IX (pdFIX) and their implications for dosing. PK data were compiled from 17 published studies. The average clearance (CL) of rFIX normally ranged between 7.5 and 9.1 mL h-1 kg-1, whereas that of pdFIX was 3.8-5.4 mL h-1 kg-1. The average terminal half-life was 18-24 h among all 72-h studies on rFIX, in contrast to (normally) 29-43 h for pdFIX. In vivo recovery was more variable. Judging from the pooled data, the typical recovery of rFIX is around two-third that of pdFIX. The difference in PK between rFIX and pdFIX is thus clear-cut and has implications for dosing. As estimated from the compiled data, the dose required to reach any peak level of FIX immediately after administration would be 1.5 times higher for rFIX than for pdFIX, most probably with considerable individual variation. Calculated doses for a patient on a twice weekly prophylactic treatment to achieve a predetermined trough FIX level depended markedly on CL and were about twice as high with rFIX as with pdFIX. In summary, conversion factors between rFIX and pdFIX of 1.5 for single doses and 2 for prophylactic dosing can tentatively be applied; however, the interindividual variance both in recovery and CL of rFIX and pdFIX and the unknown variance in ratios between these PK parameters call for careful monitoring if a switch of treatment is made.
|
|
| 23. |
|
|
| 24. |
- Björkman, Sven
(author)
-
Limited blood sampling for pharmacokinetic dose tailoring of FVIII in the prophylactic treatment of haemophilia A
- 2010
-
In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16:4, s. 597-605
-
Journal article (peer-reviewed)abstract
- Summary. The aim of this study was to evaluate the use of limited blood sampling and Bayesian analysis to estimate the pharmacokinetics (PK) and tailor the dose of factor VIII (FVIII) in an individual patient. In a Bayesian analysis, PK parameters are estimated from only a few plasma concentration measurements, using a previously established PK model. First the necessary model was created using intense blood sampling FVIII data from 10 patients. Then FVIII data from another 21 patients were used for 'clinical' evaluation. Three scenarios were created retrospectively by reduction of the original 7-sample data set; blood sampling at 4, 24 and 48 h, at 8 and 30 h and at 24 h after the infusion. PK parameters were estimated for each individual using Bayesian analysis and compared with those obtained using conventional methods from the full data. The accuracy of predictions of FVIII levels during prophylactic treatment 5-17 months later and implications for dose tailoring were also investigated. Blood sampling at 4, 24 and 48 h was found to give practically the same PK information as a full, conventional (7-10-sample) study. Even a single 24-h FVIII level provided adequate data for initial dose tailoring and gave predictions of FVIII levels 5-17 months later that were not appreciably worse than predictions based on the full PK analysis. By contrast, dose tailoring based on body weight failed completely. In conclusion, PK-based dose tailoring of FVIII can be performed using limited blood sampling during prophylactic treatment.
|
|
| 25. |
|
|
