RFVIIa transported from the blood stream into tissues is functionally active.

Abstract

Recombinant factor VIIa (rFVIIa) is used widely as an effective hemostatic agent for treatment of severe hemophilia patients with inhibitors against FVIII or FIX. Recent reports have shown that rFVIIa when administered in prophylaxis can prevent the development of mild-moderate joint bleedings [1–7]. Given the short biological half-life of rFVIIa, it is unclear by what mechanism rFVIIa could be effective in prophylactic treatment. A recent study characterizing the bio-distribution of pharmacologically administered rFVIIa by immunohistochemistry revealed that rFVIIa (1) readily associates with the endothelium, (2) enters in to extravascular tissues where it can bind to TF, and (3) remain there for longer time periods than in the circulation [8]. Although these immunohistochemistry data provide convincing evidence that rFVIIa from the blood stream enters into extravascular compartments, they provide no quantification of the amount of rFVIIa transferred from the blood stream to extravascular tissues, and no information regarding the functional status of rFVIIa associated with these tissues. Moreover, recent studies of Hoffman et al. [9] indicated that perivascular TF is occupied by endogenous FVII/FVIIa in the absence of injury. In such scenario, the exogenously administered rFVIIa may be simply supplanting the endogenous FVII/FVIIa bound to peri/extravascular tissues without increasing the net levels of FVIIa in tissues. Therefore, we thought it was important to evaluate FVIIa levels in tissues following its administration in order to assess the extent of rFVIIa transfer from the blood stream into tissues, and the functional status of rFVIIa associated with extravascular tissues.