Clot Formation in Recombinant Factor VIIa Treated Plasma (2009)
Undergraduate: Brittany Larson
Faculty Advisor: Alisa Wolberg
Department: Chemistry
Background: Hemophilia is a bleeding disorder characterized by individuals who lack or have inhibitors to Factors VIII or IX, proteins necessary for stable fibrin formation.
Recombinant factor VIIa (rFVIIa), a therapeutic that treats bleeding in hemophilic patients with inhibitors, binds to the phospholipid surface of platelets and propagates coagulation. Response to rFVIIa varies. NN1731 and NN7128 are rFVIIa-variants.
Objective: Examine the procoagulant activity of rFVIIa with respect rFVIIa-variants, presence or absence of platelets, and the source of tissue factor (Innovin or monocyte TF).
Results: RFVIIa, NN1731, and NN7128 each enhanced the procoagulant activity of hemophilic plasma: an increase in recombinant protein concentration corresponded to a decrease in onset and an increase in clot formation rate. In rFVIIa-treated plasma, regardless of the TF source, procoagulant activity increased as phospholipid concentrations increased. Innovin-treated systems normalized clot formation at lower phospholipid concentrations than monocyte-based models. Clots formed at slower rates in platelet rich plasma when compared with platelet poor plasma.
Conclusions: The findings suggest that NN1731 and NN7128 have potential clinical utility, and that phospholipid concentration influences the onset and clot formation rate of rFVIIa-dependent plasma. These in vitro clotting assays may help develop tests for individualizing dosing and detecting non-responders.