Haemophilia B - Diagnostic Insights, Genetic Aspects and Clinical Outcomes

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Haemophilia B (HB) is a rare inherited bleeding disorder caused by the deficiency of coagulation factor IX (FIX). The major clinical issues are bleedings, often targeting the joints, and the development of neutralising antibodies, i.e. inhibitors, to the FIX replacement therapy. Historically HB has been seen as identical to the more common haemophilia A (HA), i.e. deficiency of coagulation factor VIII (FVIII), but important differences between the two diseases exist. As a result of the rarity of HB, much of our knowledge of HB has been extrapolated from what is known about HA. To improve the care for persons with HB (PwHB), studies focusing on HB are of importance. The aim of this thesis was to characterise HB regarding its diagnostic challenges, treatment, clinical outcomes, and the quality of life of PwHB, and to compare some of these aspects to those of HA.

Paper I describes the comparison of the one-stage and the chromogenic assays in measuring the FIX activity level. In HA, a discrepancy between the two methods in measuring FVIII has been reported in approximately one-third of persons with non-severe HA; however, this has not previously been evaluated in HB. We found that 25% of persons with non-severe HB had discrepant results between the two methods, with higher values recorded when the chromogenic method was used. All but one of these persons had the same FIX gene (F9) mutated amino acid. This was the first study to show that assay discrepancy occurs in HB and we concluded that both the one-stage and the chromogenic assays are needed for the correct diagnosis and classification of HB.

Papers II-IV describe a cohort of 79 persons with severe HB from the Nordic countries, and 79 matched controls with HA.
In Paper II, joint assessment using ultrasound and haemophilia joint health score (HJHS) was conducted and showed that despite the fact that 95% of PwHB were treated with prophylaxis, 37% reported joint bleedings during the prior year. Ultrasound scores were overall low and HJHS scores were significantly lower among PwHB compared with persons with HA (PwHA), indicative of a milder arthropathy in patients with severe HB than in PwHA. Treatment adherence was evaluated using Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS) questionnaires and showed overall good adherence.

Paper III presents information on F9 variants, inhibitors, and immune tolerance induction (ITI) therapy in PwHB. We found a high proportion of severe F9 gene defects and a relatively high prevalence of inhibitors of 15%. Of inhibitor patients, 92% had experienced allergic manifestations and 25% nephrotic syndrome. ITI success was independent of the F9 variant and was attained despite allergic reactions and previous ITI failures. Immunosuppression included in the ITI regimen showed a high beneficial rate and may enhance the chances of success. Analyses of noninhibitory anti-FIX antibodies (NNAs) with a multi analyte profiling-based fluorescence immunoassay (xFLI) and an enzyme-linked immunosorbent assay (ELISA) were conducted, but no NNAs were identified.

In Paper IV, health-related quality of life (HRQoL) was assessed using the EQ 5D 3L questionnaire and showed a high frequency of pain, mobility problems and anxiety/depression in PwHB, indicating that areas of insufficient care exist. No significant differences in HRQoL between PwHB and PwHA were found, and impaired joint health assessed by the HJHS was found to have a significant negative impact on HRQoL.
Tilldelande institution
  • Institutionen för translationell medicin
  • Astermark, Jan, handledare
  • Gretenkort Andersson, Nadine, Biträdande handledare
  • Berntorp, Erik, Biträdande handledare
Tilldelningsdatum2023 maj 25
ISBN (tryckt)978-91-8021-410-0
StatusPublished - 2023

Bibliografisk information

Defence details
Date: 2023-05-25
Time: 09:00
Place: Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö. Zoom: https://lu-se.zoom.us/j/63684075620
External reviewer(s)
Name: Makris , Michael
Title: Professor
Affiliation: University of Sheffield, UK

Ämnesklassifikation (UKÄ)

  • Hematologi


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