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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2374-2381
The Contribution of the Three Hypothesized Integrin-Binding Sites in
Fibrinogen to Platelet-Mediated Clot Retraction
Michael M. Rooney,
David H. Farrell,
Bettien M. van Hemel,
Philip
G. de Groot, and
Susan T. Lord
From the Departments of Chemistry and Pathology and Laboratory
Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;
the Department of Biochemistry and Molecular Biology, Pennsylvania
State University, College of Medicine, Hershey, PA; and the Department
of Haematology, University Hospital Utrecht, Utrecht, The Netherlands.
Fibrinogen is a plasma protein that interacts with integrin
 IIb 3 to mediate a variety of platelet
responses including adhesion, aggregation, and clot retraction. Three
sites on fibrinogen have been hypothesized to be critical for these
interactions: the Ala-Gly-Asp-Val (AGDV) sequence at the
C-terminus of the  chain and two Arg-Gly-Asp (RGD) sequences in the
A chain. Recent data showed that AGDV is critical for platelet
adhesion and aggregation, but not retraction, suggesting that either
one or both of the RGD sequences are involved in clot retraction. Here
we provide evidence, using engineered recombinant fibrinogen, that no
one of these sites is critical for clot retraction; fibrinogen lacking
all three sites still sustains a relatively normal, albeit delayed,
retraction response. Three fibrinogen variants with the following
mutations were examined: a substitution of RGE for RGD at position A
95-97, a substitution of RGE for RGD at position A 572-574, and a
triple substitution of RGE for RGD at both A positions and deletion
of AGDV from the chain. Retraction rates and final clot sizes after
a 20-minute incubation were indistinguishable when comparing the A
D97E fibrinogen or A D574E fibrinogen with normal recombinant
fibrinogen. However, with the triple mutant fibrinogen, clot retraction
was delayed compared with normal recombinant fibrinogen. Nevertheless,
the final clot size measured after 20 minutes was the same size as a
clot formed with normal recombinant fibrinogen. Similar results were
observed using platelets isolated from an afibrinogenemic patient,
eliminating the possibility that the retraction was dependent on
secretion of plasma fibrinogen from platelet -granules. These findings indicate that clot retraction is a two-step process, such that
one or more of the three putative platelet binding sites are important
for an initial step in clot retraction, but not for a subsequent step.
With the triple mutant fibrinogen, the second step of clot retraction,
possibly the development of clot tension, proceeds with a rate similar
to that observed with normal recombinant fibrinogen. These results are
consistent with a mechanism where a novel site on fibrin is involved in
the second step of clot retraction.
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