Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4186-4194
Modulation by Heparin of the Interaction of the A1 Domain of von
Willebrand Factor With Glycoprotein Ib
Christelle Perrault,
Nadine Ajzenberg,
Paulette Legendre,
Ghassem Rastegar-Lari,
Dominique Meyer,
Jose A. Lopez, and
Dominique Baruch
From INSERM U143, Hopital de Bicetre, Bicetre, France; and the
Departments of Internal Medicine and Molecular and Human Genetics,
Baylor College of Medicine, Houston, TX.
The conformation of the A1 domain of von Willebrand factor (vWF) is
a critical determinant of its interaction with the glycoprotein (GP)
Ib/V/IX complex. To better define the regulatory mechanisms of vWF A1
domain binding to the GPIb/V/IX complex, we studied vWF-dependent
aggregation properties of a cell line overexpressing the GPIb
,
GPIb
, and GPIX subunits (CHO-GPIb/IX cells). We found that
CHO-GPIb/IX cell aggregation required the presence of both
soluble vWF and ristocetin. Ristocetin-induced CHO-GPIb/IX cell
aggregation was completely inhibited by the recombinant VCL fragment of vWF that contains the A1 domain. Surprisingly, the substitution of heparin for ristocetin resulted in the formation of
CHO-GPIb/IX cell aggregates. Using monoclonal antibodies blocking
vWF interaction with GPIb/V/IX or mocarhagin, a venom metalloproteinase
that removes the amino-terminal fragment of GPIb extending from aa 1 to 282, we demonstrated that both ristocetin- and heparin-induced
aggregations involved an interaction between the A1 domain of vWF and
the GPIb subunit of the GPIb/V/IX complex. The involvement of
heparin in cell aggregation was also demonstrated after treatment of
heparin with heparinase that abolished CHO-GPIb/IX cell
aggregation. These results indicated that heparin was able to induce
vWF-dependent CHO-GPIb/IX cell aggregation. In conclusion, we
demonstrated that heparin is capable of positively modulating the vWF
interaction with the GPIb/V/IX complex.
