Platelet activity of high‐dose factor VIIa is independent of tissue factor

TLDR

High‑dose recombinant factor VIIa is an effective haemostatic therapy for haemophiliacs with inhibitors, yet its mechanism—whether tissue‑factor dependent or independent—remains debated. We found that factor VIIa binds weakly to activated platelets, initiates thrombin generation independently of tissue factor at concentrations matching clinical efficacy, indicating it acts on the platelet plug without systemic coagulation activation.

Abstract

High‐dose recombinant factor VIIa has been successfully used as therapy for haemophiliacs with inhibitors. The mechanism by which high‐dose factor VIIa supports haemostasis is the subject of some controversy. Postulating a mechanism in which activity is dependent on tissue factor at the site of injury explains the localization of activity but not the requirement for high doses. Postulating a mechanism in which factor VIIa acts on available lipid independently of tissue factor explains the requirement for high doses but not the lack of systemic procoagulant activity. We report that factor VIIa bound weakly to activated platelets ( K d ∼ 90 n m ). This factor VIIa was functionally active and could initiate thrombin generation in the presence of plasma concentrations of prothrombin, factor X, factor V, antithrombin III and tissue factor pathway inhibitor. The activity was not dependent on tissue factor. The concentration of factor VIIa required for detectable thrombin generation agreed well with the lowest concentration of factor VIIa required for efficacy in patients. High‐dose factor VIIa may function on the activated platelets that form the initial haemostatic plug in haemophilic patients. These observations are in agreement with clinical trials which have shown that high‐dose factor VIIa was haemostatically effective without causing systemic activation of coagulation.