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

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 (Kd ∼ 90 nm). 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.

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

“…To our knowledge, there have not been previous reports of FVIIa inside platelets. In 1997, Monroe and colleagues 41,42 reported that rFVIIa could weakly bind to the membrane of activated platelets, where it could promote thrombin generation, but no reference was made to a possible presence of FVIIa inside platelets. Under physiological conditions, levels of FVIIa in plasma are very low (approximately 1% of the total circulating FVII).…”

Experiences with recombinant FVIIa in the emergency treatment of patients with autoimmune thrombocytopenia: a review of the literature

“…In vitro experiments have demonstrated that high concentrations of FVIIa induce platelet activation, generate platelet surface factor IXa and Xa which lead to thrombin generation on the platelet surface, and also to the formation of hemostatic plaque despite low platelet numbers [22,34]. Moreover, very high concentrations of rFVIIa may also result in a saturation of all available tissue factor exposed at the site of injury, as well as in extravascular spaces, leading to local thrombin generation and thrombus formation [38].…”

Activation of platelets in whole blood by recombinant factor VIIa by a thrombin‐dependent mechanism

“…Because of the dilution of blood proteins, including factor VII, in our reaction system, one might have expected to see significant platelet activation at lower concentrations of rFVIIa. An alternative or perhaps complementary explanation may be that, as rFVIIa is reported to have a lower affinity for activated platelet surfaces than for TF, relatively high rFVIIa concentrations are required (Monroe et al, 1997).…”

“…Several reports have indicated that high-dose rFVIIa can activate factors IX and X on the surface of platelets by a mechanism independent of TF (Monroe et al, 1997Hoffman et al, 1998). These observations may help to explain the efficacy of rFVIIa in the treatment of haemophilia A and B.…”

“…It has been argued that such levels are necessary in order to overcome the inhibitory effect of the inactive factor VII zymogen (van't Veer et al, 2000). However, an alternative hypothesis is that factor VIIa has a much lower affinity for binding to activated platelets than to TF (Monroe et al, 1997).…”