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J. Biol. Chem., Vol. 266, Issue 27, 17815-17820, 09, 1991
M Nesheim, DD Pittman, AR Giles, DN Fass, JH Wang, D Slonosky and RJ Kaufman
The binding of 35S-labeled recombinant human Factor VIII to activated human
platelets was studied in the presence and absence of exogenous plasma von
Willebrand factor. In the absence of added von Willebrand Factor, platelets
bound 210 molecules of Factor VIII/platelet when the unbound Factor VIII
concentration was 2.0 nM (Kd = 2.9 nM). As the von Willebrand factor
concentration was increased, the number of Factor VIII molecules
bound/platelet decreased to 10 molecules of Factor VIII bound/platelet at
24 micrograms/ml of added vWF. Addition of an anti- vWF monoclonal antibody
that inhibits the vWF-Factor VIII interaction attenuated the ability of vWF
to inhibit binding of Factor VIII to platelets. In contrast, addition of a
control anti-vWF antibody that does not block the vWF-Factor VIII
interaction did not affect the ability of vWF to inhibit Factor VIII
binding to platelets. From the vWF concentration dependence of inhibition
of Factor VIII-platelet binding, a dissociation constant for the Factor
VIII-vWF interaction was calculated (Kd = 0.44 nM). To further elucidate
the role that vWF may play in preventing the interaction of Factor VIII
with platelets, the platelet binding properties of a Factor VIII deletion
mutant (90- 73) which lacks the primary vWF-binding site was studied. The
binding of this mutant was unaffected by added exogenous vWF. These
observations demonstrate that Factor VIII can interact with platelets in a
manner independent of vWF but that excess vWF in plasma can effectively
compete with platelets for the binding of Factor VIII. In addition, since
cleavage of Factor VIII by thrombin separates a vWF- binding domain from
Factor VIIIa, we propose that activation of Factor VIII by thrombin may
elicit release of activated Factor VIII from vWF and thereby make it fully
available for platelet binding.
The effect of plasma von Willebrand factor on the binding of human factor VIII to thrombin-activated human platelets
Department of Medicine, Queen's University, Kingston, Ontario.
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