An Update on Laboratory Diagnostics in Haemophilia A and B

Jens Müller; Wolfgang Miesbach; Florian Prüller; Thomas Siegemund; Ute Scholz; Ulrich J. Sachs; Standing Commission Labor (STAEKOLA) of the Society of Thrombosis and Haemostasis Research (GTH)

doi:10.1055/a-1665-6232

Hämostaseologie, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Hamostaseologie 2022; 42(04): 248-260
DOI: 10.1055/a-1665-6232

Review Article

An Update on Laboratory Diagnostics in Haemophilia A and B

Jens Müller

¹Institute for Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany

,

Wolfgang Miesbach

²Department of Haemostaseology and Hemophilia Center, Medical Clinic 2, Institute of Transfusion Medicine, University Hospital Frankfurt, Frankfurt, Germany

,

Florian Prüller

³Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

,

Thomas Siegemund

⁴Division of Hemostaseology, Department of Medicine, University Hospital Leipzig, Leipzig, Germany

,

Ute Scholz

⁵Center of Hemostasis, MVZ Labor Leipzig, Leipzig, Germany

,

Ulrich J. Sachs

⁶Department of Thrombosis and Haemostasis, Giessen University Hospital, Giessen, Germany

,

Standing Commission Labor (STAEKOLA) of the Society of Thrombosis and Haemostasis Research (GTH)

› Institutsangaben

Abstract

Haemophilia A (HA) and B (HB) are X-linked hereditary bleeding disorders caused by lack of activity of coagulation factors VIII (FVIII) or IX (FIX), respectively. Besides conventional products, modern replacement therapies include FVIII or FIX concentrates with an extended half-life (EHL-FVIII/FIX). Two main strategies for measuring plasma FVIII or FIX activity are applied: the one-stage clotting assay (OSCA) and the chromogenic substrate assay (CSA), both calibrated against plasma (FVIII/FIX) standards. Due to the structural modifications of EHL-FVIII/FIX, reagent-dependent assay discrepancies have been described when measuring the activity of these molecules. Assay discrepancies have also been observed in FVIII/FIX gene therapy approaches. On the other hand, nonfactor replacement by the bispecific antibody emicizumab, a FVIIIa-mimicking molecule, artificially shortens activated partial thromboplastin time–based clotting times, making standard OSCAs inapplicable for analysis of samples from patients treated with this drug. In this review, we aim to give an overview on both, the currently applied and future therapies in HA and HB with or without inhibitors and corresponding test systems suitable for accompanying diagnostics.

Zusammenfassung

Bei der Hämophilie A (HA) und B (HB) handelt es sich um X-chromosomal vererbte Blutungsstörungen, die durch einen Mangel an Aktivität der Gerinnungsfaktoren VIII (FVIII) bzw. IX (FIX) verursacht werden. Im Rahmen entsprechender Substitutionstherapien kommen heute auch FVIII- oder FIX-Konzentrate mit einer verlängerten Halbwertszeit (EHL-FVIII/FIX) zum Einsatz. Zur Bestimmung der Aktivität von FVIII- bzw. FIX werden zwei grundlegend verschiedene Testprinzipien angewandt, Einstufen-Gerinnungstests (One-Stage Clotting Assay [OSCA]) und chromogene Testverfahren (CS-Assays [CSA]), welche gegen plasmatische Faktoren kalibriert werden. Aufgrund der strukturellen Modifikationen von EHL-FVIII/FIX sind testabhängige Diskrepanzen bei der Bestimmung der Aktivität dieser Moleküle beschrieben worden. Solche Diskrepanzen wurden auch im Rahmen der FVIII-/FIX-Gentherapie beobachtet. Unter Emicizumab, einem bispezifischen, monoklonalen Antikörper zur Behandlung der HA, sind die Gerinnungszeiten der aktivierten partiellen Thromboplastinzeit (aPTT) artifiziell verkürzt. Dadurch sind etablierte, aPTT-basierte Einstufen-Gerinnungstests für die Analyze von Proben von Patienten unter Emicizumab nicht anwendbar. Mit dieser Übersichtsarbeit soll ein Überblick sowohl über die Prinzipien der derzeit angewandten und zukünftigen Therapieoptionen als auch über entsprechende Testverfahren in der HA und HB gegeben werden.

Keywords

haemophilia A/B - factor concentrates - extended half-life products - emicizumab - gene therapy

Schlüsselwörter

Hämophilie A/B - Faktorenkonzentrate - verlängerte Halbwertszeit - Emicizumab - Gentherapie

Volltext

Referenzen

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