Discrepancy between one-stage and chromogenic factor VIII activity assay results can lead to misdiagnosis of haemophilia A phenotype

Summary

Severity of bleeding phenotype in hemophilia A (HA) depends on the underlying mutation in the F8 gene and, ultimately, on the concentration and functional integrity of the factor VIII (FVIII) protein in circulating plasma. Initial diagnosis for HA and monitoring of treatment is typically performed by measuring of FVIII activity by either one-stage assay or chromogenic assay.

We review evidence for why both types of assay do not give comparable results in a significant proportion of patients with non-severe haemophilia A and why the discrepancy in results between both methods segregates with distinct subclasses of known missense mutations causing haemophilia A. The current understanding of the mechanistic basis for how FVIII:C assay discrepancies arise are discussed.

Conclusion

We propose that both methods should be used in initial patient diagnosis along with follow-up genetic analysis to avoid potential misdiagnosis and to optimize treatment monitoring of patients with HA phenotypes.

Zusammenfassung

Bei Patienten mit Hämophilie A (HA) ist der Schweregrad der Blutungsneigung abhängig von der Mutation im Faktor-8-Gen sowie der Konzentration und der funktionellen Integrität des Faktor-VIII-Proteins im Blutplasma. Die anfängliche Diagnose der HA und die Therapiekontrolle erfolgen normalerweise durch Messung der FVIII-Aktivität, entweder mit Hilfe des Einstufen-Tests (one-stage assay) oder des chromogenen Zwei-Stufen Tests (two-stage assay).

Wir fassen Beobachtungen zusammen, warum die beiden Tests bei einem signifikanten Anteil der Patienten mit leichter oder mittelschwerer HA unterschiedliche Werte liefern. Die Diskrepanz zwischen beiden Testmethoden ist mit bestimmten HA-verursachenden Missense-Mutationen assoziiert. Das gegenwärtige Verständnis der Mechanismen, die zu einer solchen Assay-Diskrepanz führen, wird in diesem Review diskutiert.

Schlussfolgerung

Wir schlagen vor, dass bei der initialen Diagnosestellung beide Methoden sowie eine molekulargenetische Analyse durchgeführt werden sollten, um eine potenzielle Fehldiagnose zu verhindern und die Überwachung der Behandlung von HA-Patienten zu optimieren.

Keywords

Assay discrepancy - FVIII:C - haemophilia A - factor 8 gene mutations

Schlüsselwörter

Assay-Diskrepanz - FVIII:C - Hämophilie A - Faktor-8-Gen-Mutationen

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