Tissue Factor and Factor VIIa as Therapeutic Targets in Disorders of Hemostasis

Abstract

For hemophilia patients with inhibitors against FVIII or FIX, the development of recombinant factor VIIa (rFVIIa) raises the possibility of a therapeutic alternative whose availability and convenience of treatment are comparable to those of FVIII or FIX. In support of this new concept for the treatment of bleeding episodes, pharmacological doses of FVIIa have been shown to induce hemostasis. Pharmacological doses of rFVIIa enhance thrombin generation on thrombin-activated platelets, thereby facilitating the formation of strong, well-structured fibrin plugs resistant to premature proteolysis. Modified rFVIIa molecules with a stronger hemostatic potential have been produced. Inhibition of the FVII-TF-dependent pathway (TFPI and rFVIIai) has been tried in attempts to prevent thrombosis, with promising results in animal models so far not confirmed in clinical trials.

Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids

“…10,11 The results of the present study support the view that the rFVIIa mechanism of current pharmacologic action is more TF driven than is often described. 4,5,22 In our experiments, the inhibitory effects of FVII were observed below a 15nM concentration of rFVIIa, which lies within the concentration range of 10-25nM expected after injection of a 90 g/kg dose. 37 The existence of FVII-dependent inhibition of rFVIIa implies that the efficacy of the drug may depend on the amount of FVII in circulation because of the current dose acting in the TF-dependent range, but only if TF is exposed at low density.…”

“…10,11 Off-label use of rFVIIa for nonhemophilia patients at similar high doses indicates that the high dose required for hemophilia treatment cannot be explained by deficiencies of FVIII or FIX alone. 5,12 FVIIa is a weak enzyme and its activity requires either of 2 cofactors, tissue factor (TF) or negatively charged phospholipids. 13 Disagreement over which of the 2 cofactors explains the high pharmacologic dose of the drug has led to TF-and phospholipiddependent theories of rFVIIa action.…”

“…[1][2][3][4] The recommended dosing schedule is a supraphysiological dose of 90 g/kg every 2-3 hours until hemostasis is achieved, producing an approximately 250-fold increase above basal plasma concentrations of FVIIa (0.1 to 25nM). 5 Not only does such a treatment regimen incur a high cost, but ineffective drug responses and thrombotic complications have also been reported. [6][7][8][9] However, our current understanding of the mechanism of rFVIIa action is unclear, limiting our ability to optimize the safety and cost of treatment.…”

Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets

“…Platelet-rich plasma was obtained by centrifugation at 120 ϫ g for 15 minutes. Platelet-rich plasma aliquots were incubated with PBS, unlabeled rFVIIa (3,6,12, and 60 g/mL, final concentration), or with the same concentrations of AF488-rFVIIa, for 2 hours at 37°C, in agreement with the calculated half-life of this drug. Afterward, platelet aliquots were fixed (0.3% paraformaldehyde) and washed three times with PBS and processed for flow cytometry.…”

“…2 Notably, rFVIIa has proven useful to control active bleeding episodes not only in hemophilia, but also in other hemostatic deficiencies, including platelet and coagulation disorders. 1,3,4 The main mechanism by which rFVIIa exerts its hemostatic action in the control of active bleeding in congenital and acquired disorders of hemostasis could be explained by an enhanced thrombin generation at damaged vessels. 5,6 Tissue factor (TF) exposed at sites of vascular damage would help to localize the hemostatic response, favoring fibrin generation and platelet recruitment in more stable thrombi.…”