GTC Biotherapeutics (fka GTCB)

[DewDiligence]

Activity and Regulation of Factor VIIa Analogs with
Increased Potency at the Endothelial Cell Surface

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&l...

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J Thromb Haemost. 2006 Nov 9.

Ghosh S, Ezban M, Persson E, Pendurthi U, Hedner U, Rao LV.

Biomedical Research Division, The Univeristy of Texas Health Center at Tyler, Tyler, Texas, USA.

Variants of recombinant factor VIIa (rFVIIa) with increased intrinsic activity have been developed to improve the efficacy in treatment of bleeding disorders in future. The increased potency of FVIIa variants was demonstrated in limited in vitro and in vivo studies. However, further characterization of FVIIa variants is needed to evaluate their potential clinical use.

In the present study, we investigated the interactions of two FVIIa variants, FVIIa(Q) and FVIIa(DVQ), with plasma inhibitors, tissue factor pathway inhibitor and antithrombin, and vascular endothelium.

Both TFPI and AT/heparin inhibited the FVIIa variants more rapidly than the wild-type FVIIa in the absence of TF. In the presence of TF, TFPI, TFPI-Xa and AT/heparin inhibited FVIIa and FVIIa variants at similar rates.

Although the wild-type FVIIa failed to generate significant amounts of factor Xa on unperturbed endothelial cells, FVIIa variants, particularly FVIIa(DVQ), generated a substantial amount of factor Xa on unperturbed endothelium. Annexin V fully attenuated the FVIIa-mediated activation of factor X on unperturbed endothelial cells.

On stimulated HUVEC, FVIIa and FVIIa variants activated factor X at similar rates, and annexin V blocked the activation only partly. AT/heparin and TFPI-Xa inhibited the activity of FVIIa and FVIIa variants bound to endothelial cell TF in a similar fashion.

Interestingly, despite significant differences observed in factor Xa generation on unperturbed endothelium exposed to FVIIa and FVIIa analogs, no differences were found in thrombin generation when cells were exposed to FVIIa or FVIIa analogs under plasma mimicking conditions.

Overall the present data suggest that although FVIIa variants generate substantial amounts of factor Xa, they do not generate excessive thrombin on the surface of endothelium.
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