Influence of the γ-Carboxyglutamic Acid-Rich Domain and Hydrophobic Stack of Factor Vila on Tissue Factor Binding

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Abstract
Des(1-38)- and des(1-44)-factor Vila (fVIIa) were inhibited with Phe-Phe-Arg-chloromethyl ketone (FFR-cmk). Des(1-38)-FFR-fVIIa inhibited tissue factor (TF)-enhanced fVIIa amidolytic activity with an IC50 value of 15 nM, whereas 3-and 6-fold higher values were obtained with des(1-44)-FFR-fVIIa using soluble and full-length TF, respectively. The value for FFR-fVIIa was 8-10 nM. Clotting time was prolongated with IC50 values for inactivated des(1-38)- and des(1-44)- fVIIa of 50 nM and 1 μM, respectively, whereas FFR-fVIIa yielded a value of 10 nM. From binding experiments in a BIA-coreTM instrument, dissociation constants for the complexes between TF1-218 and fVIIa, des(1-38)-fVIIa and des(1-44)- fVIIa of about 3, 20 and 70 nM, respectively, could be estimated.

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