The Economics of Hemophilia Treatment

A graph-based machine learning framework identifies critical properties of FVIII that lead to hemophilia A

“…It circulates bound to the von Willebrand Factor (vWF), and after being activated via thrombin-mediated cleavage of some residues, it becomes detached from vWF, loses its B domain and changes into its activated form (FVIIIa) ( Childers et al, 2022 ). As co-factor for the coagulation factor IXa, FVIIIa binds to the phospholipid membrane of activated platelets and enhances its activity more than 100,000 times ( Lee et al, 2014 ). Together, they form the so-called tenase complex to activate the coagulation factor X (FX) into FXa.…”

“…Together, they form the so-called tenase complex to activate the coagulation factor X (FX) into FXa. In turn, FXa converts prothrombin to thrombin, already close to the end of the coagulation cascade [i.e., the formation of a stable fibrin clot ( Lee et al, 2014 )].…”

“…For this purpose, we used the coagulation activity and the antigen levels of 344 alanine mutations on the A2 and the C2 domains of the FVIII protein ( Pellequer et al, 2011 ; Plantier et al, 2012 ). The A2 domain is the most important domain of this protein, as it has binding sites for FIXa and for FX [the members of the tenase complex ( Lee et al, 2014 )]. Moreover, by itself, the A2 domain is able to enhance the activity of FIXa [albeit with lower efficiency compared to the full-protein ( Fay and Koshibu, 1998 ; Fay et al, 1999 )].…”

“…This is an X-linked heritable disease affecting approximately 1 in every 5,000–10,000 live male births ( Hoffbrand et al, 2016 ), and as a result, the blood coagulation cascade is impaired to different extents depending on the type of mutation on the F8 gene. Disease symptoms may vary from mild (clotting activity level 5%–40%, with only rare bleeding episodes), to moderate (clotting activity 1%–5%, more frequent episodes), and severe [clotting activity 1%, permanent bleeding risk and chronic joint damage ( Lee et al, 2014 )].…”

“…Although it is a relatively rare disorder, the coagulation pathway is well-characterized and treatment options are improving since the 1950s, evolving from blood-derived FVIII concentrates ( Lee et al, 2014 ) to recombinant proteins ( Peters and Harris, 2018 ), monoclonal antibodies ( Kitazawa et al, 2012 ; Østergaard et al, 2021 ) and gene therapy ( Nathwani, 2019 ). However, current treatment options still have major issues that have to be addressed ( Lenting et al, 2017 ), for instance, it is of paramount importance to improve the half-life of recombinant FVIII proteins (currently ∼ 12–19 h), as well as its immunogenic profile to avoid the development of neutralizing antibodies, a condition affecting 30% of patients ( Peters and Harris, 2018 ).…”