Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?

Abstract

Hemophilia A (HA) and B are inherited bleeding disorders caused by a deficiency of factor VIII or factor IX, respectively. The current standard of care is the administration of recombinant or purified factor. However, this treatment strategy still results in a high economic and personal burden to patients, which is further exacerbated by the development of inhibitors-alloantibodies to factor. The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care. Emicizumab, a bispecific antibody that mimics the function of factor VIIIa, is the first such nonfactor therapy to gain US Food and Drug Administration approval and is rapidly changing the paradigm for HA treatment. Other therapies on the horizon seek to target anticoagulant proteins in the coagulation cascade, thus "rebalancing" a hemorrhagic tendency by introducing a thrombotic tendency. This intricate hemostatic balancing act promises great things for patients in need of more treatment options, but are these other therapies going to replace factor therapy? In light of the many challenges facing these therapies, should they be viewed as a replacement of our current standard of care? This review discusses the background, rationale, and potential of nonfactor therapies as well as the anticipated pitfalls and limitations. This is done in the context of a review of our current understanding of the many aspects of the coagulation system.

Graphical abstract

Figure 1.

Coagulation cascade. A simplified representation of the “coagulation cascade”. Note the role that the tenase complexes play in thrombin generation. The intrinsic tenase complex consists of factors VIIIa, IXa, and X on a phospholipid surface with phosphatidylserine exposure, usually a platelet, and facilitates the activation of factor X. The extrinsic tenase complex consists of factor VIIa, tissue factor, and factor X, likewise leading to the activation of factor X. Note the many feedback mechanisms of activation that thrombin performs. Although the generation and exposure of TF at the site of vascular endothelial is the primary initiator of coagulation via the extrinsic pathway, the intrinsic tenase pathway is important because active TF has only limited availability in vivo and TFPI’s constitutive activity inhibits the extrinsic tenase complex from generating adequate thrombin for a stable clot (see reference 19 for a more detailed treatment of this topic). In a PTT test, a test on which clot-based factor assays are built, phospholipid and calcium are added to a sample anticoagulated with sodium citrate (a calcium chelator that inhibits the Ca++ dependent steps as noted in the figure). Thrombin is added to the assay and further generated by the thrombin burst (see text). The activation of factor VIII or IX is the rate-limiting step in the assay. Factors are labeled by their traditional roman numeral. TF, tissue factor; TFPI, tissue factor pathway inhibitor; EPCR, endothelial protein C receptor; APC, activated protein C.