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60 Part I / Basic Principles
for the same indication did not reproduce this effect (226), it is now believed that the use
of abciximab does not affect this clinical outcome (46). Nonetheless, it remains to be
determined whether other aspects of the mitogenic activity of PDGF such as matrix and
metalloprotease production (230,231) are affected by the use of GPIIb/IIIa antagonists for
other clinical indications and whether the need for revascularization is a true indication
of a smooth muscle cell proliferative response.
NEW PERSPECTIVES
FOR GPIIb/IIIa IN ANTITHROMBOTIC THERAPIES
Future directions in GPIIb/IIIa research can be expected to continue to focus on extra-
cellular and intracellular domains, providing new insights into the molecular description
of how GPIIb/IIIa interacts with its ligands, how GPIIb/IIIa is involved in the various
signal transduction pathways, and the therapeutic strategies for the regulation of GPIIb/
IIIa function. One can anticipate that the molecular crystal structure of GPIIb/IIIa will
follow closely on the recent achievement of the structure of α
V
β
3
, thus providing a con-
tour map of the GPIIb/IIIa surface and a precise description of the binding sites of this
receptor. Such information will undoubtedly yield new information on the way GPIIb/IIIa
interacts with adhesive proteins and may also provide new insights into how therapeutic
antagonists block the adhesive protein binding fuction of the integrin. It is now estab-
lished that physical aggregation is only part of GPIIb/IIIa function and that signaling in
platelets facilitates a wide range of reactions such as platelet shape change, consolidation
of aggregates, clot retraction, and, perhaps most importantly, the release or expression of
vasoactive factors.
These functions of GPIIb/IIIa indicate that it is not only involved in thrombosis and hemo-
stasis but also links platelets and platelet aggregates to coagulation, inflammation, throm-
bolysis, atherosclerosis, and the proliferation of cells in the vessel wall in a dynamic way,
more than would result from simple vessel occlusion. Evidence from both naturally occur-
ring and experimentally induced mutations of GPIIb/IIIa clearly indicates a role for the
cytoplasmic domains of GPIIb and GPIIIa in the function of GPIIb/IIIa, both in linking
the integrin to the platelet cytoskeleton and in associations with signaling proteins. Post-
aggregation tyrosine phosphorylation of the cytoplasmic domain of GPIIIa is the most
proximal signaling event in these cascades, and it is reasonable to speculate that targeting
this event may offer a new strategy for the pharmacologic intervention of GPIIb/IIIa.
Given that GPIIb/IIIa is not only involved in platelet aggregation, but also has signal-
ing functions that allow it to be vasoactive, it is reasonable to ask whether the clinical bene-
fits of GPIIb/IIIa antagonists achieved in the settings of percutaneous coronary interventions
and unstable angina were achieved solely because of the simple inhibition of occlusive
thrombi and whether additional therapeutic indications can be treated by GPIIb/IIIa antag-
onism. Is this the mechanism by which the short-term inhibition of thrombosis with GPIIb/
IIIa antagonists (e.g., <20 h) in the setting of percutaneous coronary intervention trans-
lated into a prolonged inhibition of the accrual of events (e.g., up to a year or longer), as
was observed in EPIC and ESPRIT studies (232)? Was this owing to the prevention of
release of inflammatory mediators that normally occurred by procedure-induced throm-
bosis? Another example is the use of GPIIb/IIIa antagonists in the setting of acute myocar-
dial infarction. If GPIIb/IIIa antagonists prove to be effective in this setting of acute
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Chapter 3 / GPIIb/IIIa in Platelet Aggregation 61
myocardial infarction, are they beneficial not only because of the inhibition of thrombo-
sis, but also because they prevent the release of vasoactive proteins and proinflammatory
mediators? Will more aggressive use of GPIIb/IIIa antagonists in unstable angina more
efficiently block the release of inflammatory and other vasoactive mediators and improve
the therapeutic benefit by such mechanisms? Might therapeutic indications dependent on
vascular inflammatory mediators released from platelets such as sickle cell disease, which
is accompanied by elevated sCD40L (233), also be treated with GPIIb/IIIa antagonists?
Answers to these questions might affect the future use of GPIIb/IIIa antagonists in a variety
of clinical settings.
GLOSSARY
ADP adenosine diphosphate, a platelet agonist
CD40L a membrane protein that is a ligand for CD40 and a member of the nerve
growth factor superfamily; expressed on activated platelets; CD40L
binding to CD40 results in intracellular signaling being initiated
CHO cells Chinese hamster ovary cells
CIB calcium and integrin binding protein, a protein that was identified as
associating with the cytoplasmic domain of GPIIb using a yeast two-
hybrid screen
EF hand structural motif forming a calcium binding site typified by helices E
and F of parvalbumin
FACS fluorescence-activated cell sorting
FAK focal adhesion kinase, a cytoplasmic tyrosine kinase
Fcγ a protein associated with the Fc receptor complexes Fcγ RIII and FcεRI,
which contains an ITAM (see below)
GP glycoprotein
IP
3
inositol triphosphate
ITAM immune receptor tyrosine activation motif, a consensus motif containing
two tyrosine residues that, when phosphorylated, are important in
initiating signals through a number of cell surface receptors present on
cells of the immune system
K
d
equilibrium dissociation constant
KQAGDV peptide sequence consisting of the amino acids lysine, glutamine,
arginine, glycine, aspartic acid, and valine
LIBS ligand-induced binding sites, neoepitopes expressed on GPIIb/IIIa
following the binding of ligands like fibrinogen and GPIIb/IIIa
antagonists and recognized by LIBS antibodies
Mac-1 the leukocyte integrin CD11b/CD18
MIDAS metal ion-dependent adhesion site, a structural motif identified first in
domain integrin α-subunits
M
r
apparent molecular weight of a protein determined by electrophoresis
on a reduced SDS-polyacrylamide gel
P2X1 ADP-activated ligand-gated ion channel that directly increases
intracellular calcium levels
P2Y1 ADP-activated, Gq-coupled seven-spanning transmembrane receptor
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62 Part I / Basic Principles
PAR1, PAR3 Members of the protease-activated receptor family that function as
thrombin receptors in platelets; activated by cleavage of their amino
termini, leading to the exposure of a new amino acid sequence that acts
as a “tethered ligand” to activate the receptors
PDGF platelet-derived growth factor
PKC protein kinase C
Pl
A2
a GPIIb/IIIa isotype
PLA
2
phospholipase A
2
PLC phospholipase C, a phospholipase isoform that when activated can
lead to phosphoinositide hydrolysis, diacylglycerol production, and
increases in intracellular calcium levels
Raf-1 a serine/threonine kinase
RGD peptide sequence consisting of the amino acids arginine, glycine, and
aspartic acid
SHC/GRB2 two adaptor proteins capable of binding to phosphotyrosine residues of
signaling proteins; SHC can associate with GRB2, which can then
associate with SOS (see below), linking cell surface receptors to the
Ras signaling pathway
SOS son of sevenless, a guanine nucleotide exchange factor that activates Ras
Src-family a family of at least 11 cytoplasmic tyrosine kinases whose prototypic
member is Src
Syk spleen tyrosine kinase, also known as p72, a tyrosine kinase found
in hematopoietic cells; known to bind to phosphorylated tyroinse
residues in ITAM motifs via its two SH2 regions
TGF-β transforming growth factor-β
TRAP thrombin receptor activation peptide, a peptide corresponding to the
amino acid sequence of the “tethered ligand” of the PAR1 thrombin
receptor; this peptide can activate PAR1 in the absence of thrombin
cleavage
TXA
2
thromboxane A
2
VWF von Willebrand factor
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