Correlation analysis of standard Bethesda method versus modified Nijmegen assay in detecting factor VIII inhibitors, and impact of marginal titer inhibitors on FVIII pharmacodynamics and pharmacokinetics by patients with hemophilia A
Authors:
A. Morongová 1; D. Jankovičová 1; A. Bátorová 1; T. Prigancová 1; E. Khúnová 1; I. Waczulíková 2; M. Skraková 1; M. Mistrík 1
Authors‘ workplace:
Klinika hematológie a transfuziológie LF UK, SZU, Univerzitná nemocnica Bratislava
1; Fakulta matematiky, fyziky a informatiky Univerzity Komenského Bratislava
2
Published in:
Transfuze Hematol. dnes,22, 2016, No. 3, p. 172-181.
Category:
Comprehensive Reports, Original Papers, Case Reports
Overview
Inhibitors of FVIII represent serious complication of hemophilia A resulting in the ineffectiveness of replacement therapy. Classical Bethesda method and Nijmegen modification are used for an inhibitor detection. We performed correlation analysis of inhibitors titres investigated by both methods and we evaluated an impact of marginal/low inhibitor titres on pharmacodynamics (in vivo recovery and incremental response of FVIII) and pharmacokinetics (half life-T1/2 and clearance) after intravenous administration of FVIII. We compared the results of 265 parallel inhibitor measurements by Bethesda and Nijmegen assay performed in 77 severe hemophilia A patients; out of them 60 patients with the negative history of inhibitors (Group 1) and 17 patients with history of inhibitors after immune tolerance induction (ITI) (Group 2) with partial (n = 4) and complete success (n = 13). Nijmegen method excluded the false positivity of low titer inhibitors between 0,51 and 0,9 BU/ml detected by Bethesda method and a good correlation between cut-off 0.7 Bethesda units/ml (BU/ml) and 0,5 Nijmegen BU/ml (NBU/ml) was confirmed. Comparison of 120 and 72 investigations of FVIII pharmacodynamics in Group 1 (inhibitor titre of 0,2 ± 0,1 NBU/ml) and in Group 2 (inhibitor titre 0,5 ± 0,15NBU/ml), respectively, showed in vivo recovery 109 ± 19,4 (range 60–160) % and 86 ± 32 (44–136) %, and incremental response 2,2 ± 0,7 (1,4–3,5) %/1IU/kg and 1,6 ± 0,6 (0,72–2,8) %/1 IU/kg, respectively. Twenty pharmacokinetics studies in 20 patients from Group 1 and 26 studies in 13 patients from Group 2 showed the half life 11,5 ± 1,8 h (8,2–16,2 h) and 8,14 ± 3,61 h (2.9–16.4 h), respectively, and a clearance 3,7±1,2 (2,6-6,5) ml/kg/h versus 6,48 ± 2,24 (2,9–11,9) ml/kg/h; (p < 0.05) respectively.
Conclusion:
We recommend Nijmegen assay as a reference method for inhibitor testing with negativity cut-off 0,5 NBU/ml. However, in several patients after ITI negative inhibitor titre does not correlate with pharmacodynamics and pharmacokinetics of FVIII. Definite evaluation of the ITI success requires further study and new methods of inhibitor detection with a higher sensitivity and specificity.
KEY WORDS:
FVIII inhibitors – Bethesda method – Nijmegen modification – cut-off – low titer inhibitors
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Transfusion and Haematology Today
2016 Issue 3
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