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Location of the platelet binding site in zymogen coagulation factor IX

The assembly of the tenase complex on the surface of the platelet is an essential step in maintaining normal hemostasis as evidenced by the serious hemorrhagic diathesis associated with either factor IX (FIX) or factor VIII deficiencies. Understanding the regions and or residues of FIX crucial for proper binding to platelets has important clinical implications. The ability of FIX to bind activated platelets in the presence of 4 mmol/l CaCl2 was examined using electrophoretic light-scattering experiments. Wild-type FIX binds to activated platelets with dissociation constant K d = 7.9 nmol/l. Activated FIX binds to activated platelets with K d = 2 nmol/l. Activated factor VII does not bind activated platelets at physiological concentrations. The Gla domain of FIX is important for the binding of FIX to activated platelets since a chimera with a factor VII (FVII) template and FIX Gla [FVII(FIXGla)] has K d = 9.6 nmol/l, and a chimera with a FVII template and FIX Gla, A and the first epidermal growth factor domain (EGF1) [FVII(FIXGla,A,EGF1)] has K d = 9.7 nmol/l, but a chimera with a FIX template and a FVII Gla [FIX(FVIIGla)] does not bind activated platelets. Altering the fifth residue of FIX from a lysine to an alanine (Lys5 ← Ala) abolishes the mutant from binding to collagen but does not affect FIX binding to the activated platelet ( K d = 9.8 nmol/l). Point mutations involved with residues 4 and 5 (Gly4 ← Phe and Lys5 ← no residue), residue 9 (Phe9 ← Ala), residue 10 (Val10 ← Lys) and residues 9–11 (Phe9 ← Met, Val10 ← Lys, Glu11 ← Lys) do not bind to activated platelets.