At 7.5 g/L of anti-antithrombin antibody (9% antithrombin residual activity), endogenous thrombin potential increased dramatically to 2716 nM.min whereas the maximum height reached 76 nM. then compared its effectiveness to generate thrombin to depletion of antithrombin or cells element pathway inhibitor by specific antibodies. Finally, we compared the kinetics of neutralization of element Xa and Gla-domainless element Xa by antithrombin and cells element pathway inhibitor. == Results == Gla-domainless element Xa was able to restore thrombin generation in plasma samples from hemophiliacs. This effect was observed for PF-4191834 plasma from hemophilia A individuals without or with inhibitors and for plasma from hemophilia B individuals. Gla-domainless element Xa had a lower affinity than element Xa for cells element pathway inhibitor whereas the affinities of both proteins for antithrombin were related. Finally, despite a short half-life in plasma, the effect of Gla-domainless element Xa on thrombin generation was sustained for at least 1 hour. == Conclusions == As Gla-domainless element Xa was able to restore thrombin PF-4191834 generation in plasma from hemophilia individuals, our results suggest that it may be an effective alternative to current treatments for hemophilia with or without an inhibitor. Keywords:Gla-domainless element Xa, FXa, TFPI, thrombin generation, hemophilia, inhibitor == Intro == Hemophilia is an X-linked bleeding disorder characterized by dysfunction of the intrinsic tenase complex because of a deficiency in coagulation element VIII (hemophilia A) or IX (hemophilia B).1In recent years, the treatment of patients with severe hemophilia has improved considerably because PF-4191834 of the higher availability of concentrates, allowing widespread adoption of prophylaxis to prevent bleeding episodes.2However, for hemophilia A in particular, the development of antibodies inhibiting the activity of the therapeutic clotting element is the most serious and costly complication of alternative therapy.3Inhibitor formation is observed in 10 to 30% of hemophilia A individuals, depending on the nature of the concentrate used,4and in 1.5 to 3% of hemophilia B individuals.5The first aim in treating the inhibitor is to eradicate it permanently by immune tolerance induction in order to be able to resume replacement therapy.6,7For individuals in whom this immune tolerance cannot be achieved and who have a high titer of inhibitors [> 5 Bethseda devices (BU)/mL)], bypassing providers are needed. FEIBA (element VIII inhibitor-bypassing activity), an activated prothrombin complex, and NovoSeven, a recombinant activated element VII (rFVIIa), are both extensively used to treat hemorrhagic episodes in individuals with inhibitors.8,9However, both these products have limitations. A randomized assessment of the two products showed that a substantial quantity of individuals do not respond to these bypassing providers.10Moreover, rare thrombotic adverse events are observed with both rFVIIa and FEIBA. 11These problems focus on the need to develop alternate restorative strategies. As emphasized by Tuddenham, the pathways involved in bypassing a clogged tenase converge for the tissue element (TF)-dependent complex that initiates coagulation.12One possible way of bypassing a blocked tenase is to increase the availability of TF through generation of TF-bearing microparticles, such as is observed following infusion of P-selectin/immunoglobulin chimera protein (as proposed by Hrachovinovet al).13Another possibility is definitely to neutralize the activity of tissue factor pathway inhibitor (TFPI). In fact, anti-TFPI immunoglobulin shortens the coagulation time of plasma from hemophiliacs14and the bleeding time in rabbits with antibody-induced hemophilia A.15In addition, additional approaches to neutralizing TFPI have been shown to be activeex vivoand in animal models.1619 Here, we propose a new approach to unlock the tenase complex of hemophilia patients CLG4B with or without inhibitor. In contrast to activated element X (FXa), Gla-domainless FXa (GDXa) is unable to bind to procoagulant phospholipids and is almost PF-4191834 completely devoid of procoagulant activity.20However, mainly because GDXa retains the capacity to bind TFPI21and the GDXa-TFPI complex is unable to inhibit the FVIIa-TF.
