The Use of Bypassing Treatment Strategies in Hemophilia and Their Effect on Laboratory Testing

Abstract

Factor VIII and IX inhibitors in congenital hemophilia A and B, respectively, neutralize the infused coagulation factor concentrate rendering them ineffective. Bypassing agents (BPAs) that circumvent the block imposed by the inhibitors are used for the prevention and management of bleeding. Activated prothrombin complex concentrate was the original BPA, recombinant activated factor VII was then introduced, and more recently nonfactor agents that target the procoagulant and anticoagulant systems have been developed and are in clinical use (e.g., emicizumab, a bispecific antibody for hemophilia A). Other BPAs are in clinical trials (e.g., fitusiran targets antithrombin, concizumab and marstacimab target tissue factor pathway inhibitor, and SerpinPC targets activated protein C). The BPAs have a varied effect on coagulation assays, and as more patients are exposed to these agents, it is important to be aware of the effects. Herein, we present an overview of the effect of BPAs on routine and specialized coagulation assays including thrombin generation and viscoelastic assays.

Clot formation and fibrinolysis assays reveal functional differences among hemostatic agents in hemophilia A plasma

“…A challenge when evaluating the available products stems from their unique mechanisms of action, which produce different and sometimes unexpected effects in assays that employ different reagents and instruments [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] ]. The modified rFVIII products retain many of the biochemical properties of native FVIII but behave differently in the presence of different activators (eg, silica or kaolin-based products) [ 13 ].…”

“…Bypassing agents that include preactivated factors circumvent conventional initiation mechanisms and interfere with 1-stage assays (clotting times). Accordingly, discrepancies between 1-stage and 2-stage clotting or chromogenic assays complicate comparisons between, and postinfusion monitoring of, FVIII replacement products [ [10] , [11] , [12] , [13] ] and bispecific antibodies [ [14] , [15] , [16] , [17] ]. The use of product-specific reference standards enables quantification of individual agents but makes it difficult to assign FVIII-equivalent values, directly compare products during preclinical development, or measure therapeutic effects in the presence of endogenous factors or when more than 1 product is on board.…”

Laboratory Diagnostics for Thrombosis and Hemostasis Testing—Part II

“…In the last manuscript, authors Pruthi and Chen discuss the bypassing agents used to treat hemophilia A and B patients with factor inhibitors, including treatments currently used and those in development. 12 The review focuses on what is known about the effects of these agents on routine and specialized coagulation assays.…”