Novel alternate hemostatic agents for patients with inhibitors



Inhibitor formation is among the most severe complications of hemophilia treatment. With a cumulative incidence of ∼30% in those with severe hemophilia A and ∼3% in those with severe hemophilia B, inhibitors are caused by a T-cell response directed against infused coagulation factor; these inhibitors neutralize factor VIII or IX activity and disrupt normal hemostasis. Inhibitor patients become unresponsive to standard factor treatment and, as an alternative, use bypass treatment (eg, recombinant factor VIIa or factor VIII inhibitor bypass activity). To get more news about medical kits, you can visit rusuntacmed.com official website.
However, response to bypass agents is poorer and the burden of disease is higher, with greater morbidity, hospitalization, cost, and mortality, than in noninhibitor patients. Furthermore, inhibitor formation interferes with prophylaxis to prevent bleeding episodes and is a contraindication to gene therapy. Thus, more effective therapies for inhibitor patients are greatly needed. In the last several years, there has been an explosion of novel alternative hemostatic agents for hemophilia patients with and without inhibitors. These agents take advantage of technologic manipulation of coagulation factors and natural anticoagulants to promote hemostasis. The approaches include the following: (1) mutants or mimics of coagulation factors, rendering them resistant to natural anticoagulants; or (2) knock-down or disruption of natural anticoagulants, preventing degradation of coagulation factors. The purpose of this article was to review these novel alternative hemostatic agents and their mechanisms of action, as well as the preliminary pharmacokinetic, safety, and efficacy data available from early-phase clinical trials.
Despite the gains made in improving the safety and half-life of coagulation factor concentrates for the treatment of individuals with hemophilia, problems remain. This scenario is particularly true for the ∼30% who develop inhibitors to factor VIII (FVIII), as inhibitors neutralize FVIII activity and disrupt normal hemostasis, requiring bypass therapy (eg, recombinant factor VIIa [rFVIIa] or factor VIII inhibitor bypass activity [FEIBA]). However, response to rFVIIa and FEIBA is less effective than standard factor in noninhibitor patients, resulting in 2-fold the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of noninhibitor patients.1,2 Furthermore, inhibitors interfere with prophylaxis to prevent bleeding episodes and are a recognized contraindication to gene therapy. Thus, simpler, more effective treatment of hemophilia inhibitor patients is needed.

In the last several years, there has been an explosion of novel alternative hemostatic agents for patients with hemophilia A and B, with and without inhibitors. These hemostatic agents, many of which are in clinical trials, show potential to simplify treatment by reducing treatment frequency, invasiveness by subcutaneous administration, and immunogenicity by avoiding factor use. Furthermore, these agents promote hemostasis in inhibitor patients comparable to that in noninhibitor patients. The mechanisms by which these hemostatic agents promote hemostasis include the following: (1) mutants or mimics of coagulation proteins (eg, FVIII, factor V, FX) to render them resistant to natural anticoagulants; or (2) knock-down or disruption of natural anticoagulants (eg, AT, tissue factor pathway inhibitor [TFPI], activated protein C [APC]) to allow unopposed hemostasis. Some of these agents take advantage of the modulating prothrombotic effects observed in patients with coagulation factor mutations (eg, factor V Leiden) or in patients with deficiencies of natural anticoagulants (eg, antithrombin deficiency). These novel agents use unique technologies to promote hemostasis by interfering with physiological regulation of coagulation, including RNA interference, bispecific monoclonal antibodies, paired basic amino acid cleaving enzyme (PACE)/furin cleavage, super-active factor mutants, zymogen-like factor variants, and serpin mutants. For each novel agent, the present article reviews the mechanism of coagulation inhibition, pharmacokinetic variables, and, where available, safety and efficacy data from early clinical trials.