New challenges and best practices for the laboratory monitoring of factor VIII and factor IX replacement

Abstract

Several recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have recently been validated by clinical studies. The availability of these novel concentrates is expected to significantly facilitate the treatment of patients with hemophilia A and B. However, the modification applied to these molecules has introduced variations in their activity measurement in routine coagulation assays. Depending on the assays, underestimations of up to 10-fold or overestimations of up to approximately 30-fold in the measurements of the recovery have been reported in some factor concentrates. Such biases in monitoring may lead to major under- or overtreatment, as well as unnecessary searching for inhibitor antibodies. In this review, we discuss the guidelines and recommendations that allow the selection of optimal strategies to monitor patients treated with these novel factor concentrates. Based on the specificities of the assays and on local regulations, different chromogenic substrate assays in addition to one-stage clotting assays may be validated to allow the accurate measurement of all novel products. An efficient communication between the clinical laboratory and the clinicians is essential to ensure that the appropriate assays are carried out in laboratories and that the clinicians correctly evaluate the data. Further laboratory and clinical studies are still required for the optimization of the laboratory assays that can be used in the measurement of novel factor VIII and factor IX concentrates with EHL.

Comparative pharmacokinetics of two extended half‐life FVIII concentrates (Eloctate and Adynovate) in adolescents with hemophilia A: Is there a difference?

“…Chromogenic assays have also been shown to be capable of monitoring FVIII levels in subjects receiving Adynovate or Eloctate, although they have been reported to yield 10% to 20% higher levels than most OSAs, particularly at higher FVIII levels (i.e. >50%) . In this study, the same was found; FVIII levels obtained (using the CA) at early time points were generally higher than those obtained with the OSA – particularly for Adynovate.…”

Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy

“…CSAs have lower interlaboratory variability, likely because they are not plasma based, and are the recommended method for potency assignments by the European Medicine Agency. However, long-recognized and well-described discrepancies exist between the factor activity measured by OSA and CSA for different FVIII and FIX molecules 145, 146, 147, 148, 149. This issue of assay discrepancy has become more prominent as bioengineered EHL FVIII and FIX molecules have entered clinical use that requires specific assays and reagents to monitor post-infusion levels 14, 149.…”

Clinical utility and impact of the use of the chromogenic vs one‐stage factor activity assays in haemophilia A and B

“…41 Ideally, the same assay type that was used to assign potency should be used to measure levels in patient's plasma. 44 Information regarding assay specifics that allow accurate measurement of product activity may be specified in the manufacturer reference materials. Laboratories and clinicians can also attempt to determine the best method for assessing the product in the patient's plasma by reviewing the available literature.…”