Insights into the thrombogenicity of Factor IXa: trace amounts of Factor IXa promote growth of clot size

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	FDA/CBER	IMAG-14

Authors

• NK Jha
• AM Shibeko
• MV Ovanesov

Abstract

Novel therapeutics targeting activated coagulation factor IX (FIXa) may suppress thrombosis without causing bleeding tendency. We hypothesized that distinct roles of FIXa in thrombosis and hemostasis are determined by spatial distribution of FIXa inside and outside of the growing clot. Light scattering videomicroscopy was used to monitor clot growth in a thin layer of human FIX-deficient plasma embedded in a low temperature gelling agarose. Contact of plasma with immobilized or liquid tissue factor (TF) induced rapid but short-living formation of clots up to 1 mm in size. Supplementation of TF with FIXa allowed for FIXa diffusion into plasma, increasing the duration of the rapid phase of clot growth. FXa diffusion had a similar but 10 times weaker effect. In contrast, subpicomolar amounts of FIXa added directly to plasma promoted clot growth at steady rates, proportionally to FIXa concentration and independently of TF concentration, resulting in a seemingly endless clot formation. We conclude that self-limiting and injury-dependent hemostatic plug formation is regulated by the rate of TF-mediated FIXa generation and diffusion from the site of injury to plasma. In contrast, trace amounts of FIXa in circulation may lead to uncontrolled clot growth that possibly explains FIXa-associated thrombus formation.

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