Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:285-289
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:285.)
© 2000 American Heart Association, Inc.
Congenital Disorders of Platelet Signal Transduction
A. Koneti Rao;
Jagadeesh Gabbeta
From the Department of Medicine and the Sol Sherry Thrombosis Research
Center, Temple University School of Medicine, Philadelphia, Pa.
Key Words: congenital platelet function disorders signal transduction defects disorders of secretion
 |
Introduction
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After injury to the blood vessel, platelets adhere to
the exposed
subendothelium by a process (adhesion) that
involves the interaction
of a plasma protein, von Willebrand
factor (vWF), and a specific
protein on the platelet surface,
glycoprotein Ib (GPIb; the
Figure

).
Adhesion is followed by
recruitment of additional platelets
that form clumps, a process
called aggregation (cohesion). This
involves binding of fibrinogen to
specific platelet surface
receptorsa complex comprising
glycoproteins IIb-IIIa
(GPIIb-IIIa). Activated
platelets release the contents of their
granules (secretion or
release reaction), such as ADP and serotonin
from dense
granules, which subsequently cause recruitment of
additional
platelets. In addition, platelets play a major role
in
coagulation mechanisms; several key enzymatic reactions occur
on the
platelet membranelipoprotein surface. A number
of
physiological agonists interact with specific
receptors on
the platelet surface to induce responses, including a
change
in platelet shape from discoid to spherical, aggregation,
secretion,
and thromboxane A
2
(TxA
2) production. Other agonists such as
prostacyclin
inhibit these responses. Ligation of the platelet
receptors
initiates the production or release of several
intracellular
messenger molecules, including Ca
2+
ions, products of phosphoinositide
(PI) hydrolysis
by phospholipase C (PLC; diacylglycerol [DG]
and inositol
1,4,5-triphosphate [InsP
3]),
TxA
2, and cyclic nucleotides
(cAMP;
the Figure

). These subsequently induce or modulate the
various
platelet responses of Ca
2+ mobilization,
protein phosphorylation,
aggregation, secretion, and
liberation of arachidonic acid.
The interaction between
the agonist receptors and the key intracellular
effector enzymes (eg,
PLA
2, PLC, adenylyl cyclase) is mediated
by a
group of GTP-binding proteins that are modulated by GTP.
As in most
secretory cells, platelet activation results in a
rise in
cytoplasmic ionized calcium concentration; InsP
3
functions
as a messenger to mobilize Ca
2+ from
intracellular stores. DG
activates protein kinase C (PKC), and
this results in the phosphorylation
of the 47-kDa
protein pleckstrin. PKC activation is considered
to play a major role
in platelet secretion and in the activation
of GP IIb-IIIa.
Numerous other mechanisms, such as phosphorylation
of
proteins by nonreceptor tyrosine kinases, also play a role
in signal
transduction. A detailed description of the platelet
activation
mechanisms is beyond the scope of this review. Inherited
or acquired
defects in the above platelet mechanisms may lead
to an impaired
platelet role in hemostasis.

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Figure 1. Schematic representation of normal platelet
responses and the congenital disorders of platelet function. Some
of the platelet-mediated coagulation protein interactions are also
shown. Coagulation proteins are shown by Roman numerals, with the
activated forms designated by the letter a. The arrows
designate conversions of zymogens to enzymes. CO indicates
cyclooxygenase; DAG, diacylglycerol; G, GTP-binding
protein; IP3, inositol trisphosphate; MLC, myosin light
chain; MLCK, myosin light-chain kinase; PIP2,
phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC,
phospholipase C; PLA2, phospholipase A2; R,
receptor; TK, tyrosine kinase; and TS, thromboxane
synthase. Other abbreviations are defined in text.
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 |
Congenital Disorders of Platelet Function
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Disorders of platelet function are characterized by highly
variable
mucocutaneous bleeding manifestations and excessive
hemorrhage
after surgical procedures or trauma. A majority of
patients,
but not all, have a prolonged bleeding time. Platelet
aggregation
and secretion studies provide evidence for the defect but
are
not always predictive of the severity of clinical manifestations.
The
platelet dysfunction in these patients arises by diverse
mechanisms.
1 2 3 The Table 1

provides a classification based
on the platelet
functions or responses that are abnormal (the
Figure

). In patients
with defects in plateletvessel wall
interactions, adhesion
of platelets to the
subendothelium is abnormal. The 2 disorders
in this
group are von Willebrand disease (vWD), due to a deficiency
or
abnormality in plasma vWF,
4 and the Bernard-Soulier
syndrome,
in which platelets are deficient in GPIb (and GPV and
IX), and
the binding of vWF to platelets is abnormal.
5
Disorders characterized
by abnormal platelet-platelet
interactions (aggregation) arise
because of a severe deficiency of
plasma fibrinogen (congenital
afibrinogenemia) or because of a
quantitative or qualitative
abnormality of the platelet membrane
GPIIb-IIIa complex (Glanzmann
thrombasthenia).
6
Patients with defects in platelet secretion
and signal transduction
are a heterogeneous group, lumped together
for convenience
of classification rather than on the basis of
an understanding of the
specific underlying abnormality. The
major common characteristic in
these patients, as currently
perceived, is an inability to release
intracellular (dense)
granule contents on activation of
platelet-rich plasma with
agonists such as ADP,
epinephrine, and collagen. In aggregation
studies, the second
wave of aggregation is blunted or absent.
A small proportion of these
patients have a deficiency of dense
granule stores (storage pool
deficiency). In some of the other
patients, the impaired secretion
results from aberrations in
the signal transduction events that govern
end responses such
as secretion and aggregation. This review will focus
on these
patients, who are encountered more often than are those with
thrombasthenia
or the Bernard Soulier syndrome. Last are the patients
who have
an abnormality in interactions of platelets with proteins
of
the coagulation system; the best described is the Scott
syndrome.
7 In addition to the aforementioned groups, there
are patients
who have abnormal platelet function associated with
systemic
disorders such as Down syndrome and the May-Hegglin anomaly,
in
which the specific aberrant platelet mechanisms are still
unclear.
 |
Disorders of Platelet Secretion and Signal
Transduction
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As a unifying theme, patients lumped in this
heterogeneous group
generally manifest impaired secretion
of granule contents and
an absence of the second wave of aggregation on
stimulation
of platelet-rich plasma with ADP and
epinephrine; responses
to collagen, thromboxane
analogue (U46619), arachidonic acid,
and
platelet-activating factor (PAF) may also be impaired. Platelet
function
is abnormal in these patients either when the granule contents
are
diminished (storage pool deficiency [SPD]) or when there is
an
aberration in the activation mechanisms governing aggregation
and
secretion (the Table

).
 |
Deficiency of Granule Stores
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The term storage pool deficiency (SPD) refers to patients with
deficiencies
in platelet content of dense granules (

-SPD),

-granules (

-SPD),
or both types of granules
(


-SPD).
3 8 The Quebec platelet disorder
is an
autosomal dominant disorder associated with abnormal proteolysis
of

-granule proteins, deficiency of platelet

-granule
multimerin
(a factor Vbinding protein), and markedly impaired
aggregation
with epinephrine as a striking
feature.
8
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Defects in Platelet Signal Transduction (Primary Secretion
Defects)
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Signal transduction mechanisms encompass processes that are
initiated
by the interaction of agonists with specific platelet
receptors
and include responses such as G-protein activation and
activation
of effectors such as PLC and PLA
2. If
the key components in
signal transduction are the surface receptors,
the G proteins,
and the effectors, then evidence now exists for
specific platelet
abnormalities at each of these levels.
Defects in Platelet-Agonist Interaction: Receptor
Defects
These patients have impaired responses because of an abnormality
in the platelet surface receptor for a specific agonist. Such
receptor defects have been documented for
epinephrine,9 collagen,10 11 12 13
ADP,14 15 16 and
TxA2.17 18 19 20 Hirata et
al17 have described an Arg 60 to Leu mutation of the human
TxA2 receptor in a dominantly inherited bleeding
disorder. Patients described by Cattaneo et al14 16 and
Nurden et al15 have a defect in the interaction of ADP
with one of its receptors. Because ADP and TxA2
play a synergistic role in platelet responses to several agonists,
patients with these receptor defects manifest abnormal responses to
multiple agonists. A few patients have been described in whom
platelet responses to collagen only are blunted and are associated
with deficiencies in membrane glycoproteins, including GPIa
and GPVI.10 11 12 13 GPVI-deficient platelets have been
reported to have impaired collagen activation of tyrosine kinase Syk
but not c-Src.21
Defects in G-Protein Activation
G proteins are a heterogeneous group of proteins
that link surface receptors and intracellular effector enzymes and
constitute an important potential aberrant locus leading to
platelet dysfunction. Convincing evidence for such a defect has
been provided by Gabbeta et al22 in a patient with a mild
bleeding disorder, abnormal aggregation and secretion responses to a
number of agonists, and diminished GTPase activity (a reflection of
G-protein
-subunit function) on activation. This patient had a
selective decrease in the platelet membrane
G
q subunit but normal levels of
G
i, G
12,
G
13, and G
z. She has
been reported to have impaired Ca2+
mobilization23 and diminished release of free
arachidonic acid from phospholipids on platelet
activation.24 Essentially identical abnormal platelet
findings have been reported in the
G
q-deficient knockout mouse.25
Impaired G-protein activation has also been reported in patients with
the TxA2 receptor defect.18 19
Defects in Phospholipase C Activation, Calcium Mobilization,
Pleckstrin Phosphorylation, and Tyrosine
Phosphorylation
Several patients have been identified who have a relatively
mild bleeding diathesis and impaired dense granule secretion, although
their platelets have normal granule stores and, in general,
synthesize substantial amounts of
TxA2.26 27 These patients have
abnormal aggregation and secretion particularly in response to weaker
agonists (ADP, epinephrine, and PAF); the response to
relatively stronger agonists such as arachidonate and high
concentrations of collagen may be normal. Such patients are far more
common than those with SPD or defects in TxA2
synthesis. Lages and Weiss26 have described 8 such
patients who had decreased initial rates and extents of aggregation in
response to ADP, epinephrine, and U44169. Defects in early
platelet-activation events were postulated in these patients. They
subsequently demonstrated in one of these patients a defect in
phosphatidylinositol hydrolysis and phosphatidic acid
formation,28 and pleckstrin
phosphorylation.29
An early response to platelet stimulation is the rise in
cytoplasmic Ca2+ concentration. Therefore,
attention has been focused on this process to explain the impaired
aggregation and secretion. In several patients, defects in calcium
mobilization have been proposed on the basis of impaired platelet
responses to the calcium ionophore A231871 ; however, this
evidence is indirect at best. Direct evidence has been provided that
some of these patients have impaired Ca2+
mobilization on platelet activation.23 30
Detailed studies in 2 patients with impaired aggregation and secretion
revealed that the resting cytoplasmic Ca2+
concentration was normal but the peak Ca2+
concentrations after activation with ADP, collagen, PAF, or thrombin
were diminished,30 with abnormalities in both the release
of Ca2+ from intracellular stores and the influx
of extracellular Ca2+.23 Further
studies showed a defect in platelet formation of
InsP3 (the key intracellular mediator of
Ca2+ release) and DG and in pleckstrin
phosphorylation,31 indicating a defect in
PLC activation. Human platelets contain at least 7 PLC isozymes in
the quantitative order
PLC-
2>PLC-ß2>PLC-ß3>PLC-ß1>PLC-
1>
PLC-
1>PLC-ß4.32 Studies in 1 of these patients
revealed a selective deficiency in PLC-ß2 with normal levels of other
PLC isoforms.32 These studies provide strong evidence that
PLC-ß2, a G proteinlinked PLC isozyme, plays a major
physiological role in platelet responses to
activation. In line with these studies, knockout mice deficient in
PLC-ß2 have impaired Ca2+ mobilization in
neutrophils.33
Several other studies provide evidence for defects in signaling
mechanisms, phosphatidylinositol metabolism, and protein
phosphorylation in patients with abnormal platelet
aggregation and secretion.28 29 34 35 Holmsen et
al34 described a patient with abnormal platelet
aggregation and dense granule secretion who had impaired release of
free arachidonic acid and
phosphoinositide hydrolysis on thrombin activation.
However, no studies were performed on Ca2+
mobilization or Ins1,4,5P3 production,
and the platelets had reduced GPIIb and IIIa as well. Another
patient has been described with impaired platelet responses and
diminished phosphoinositide metabolism in
whom the altered stimulus-response coupling has been attributed to
abnormal membrane phospholipid composition.36 Fuse et
al19 have reported a patient with a mild bleeding disorder
whose platelets had impaired aggregation, secretion,
InsP3 formation, and Ca2+
mobilization in response to a TxA2 mimetic
(STA2) associated with normal
TxA2 formation. Interestingly, GTPase activity on
activation with STA2 was also impaired, leading
to the conclusion that the platelets had an abnormality in coupling
between the TxA2 receptor and PLC. In the patient
described by Mitsui,35 the abnormal platelet
aggregation was associated with decreased
TxA2-induced InsP3
formation but with normal TxA2 receptors and
GTPase activity on stimulation with TxA2 analogue
U46619, suggesting an abnormality in PLC activity downstream from the
receptor. In an analysis of 5 patients with absent
TxA2-induced aggregation, Fuse et
al20 found evidence for a receptor defect in 3 patients;
in the other 2, the primary abnormality appeared distal to the
receptor. Together the above studies provide evidence for abnormalities
in signal transduction pathways in patients with diminished
platelet aggregation and secretion responses.
Yang et al27 have summarized detailed studies on signaling
mechanisms in 8 patients with abnormal aggregation and secretion in
response to several different surface receptormediated agonists
despite the presence of normal dense granule contents. Both PKC-induced
pleckstrin phosphorylation and cytoplasmic
Ca2+ mobilization play a major role in
aggregation/secretion on activation. Receptor-mediated
Ca2+ mobilization and/or pleckstrin
phosphorylation was abnormal in 7 of the patients. It
was postulated that combined platelet activation with a
cell-permeable direct PKC activator,
1,2-dioctanoyl-sn-glycerol, and ionophore A23187, which
possibly bypasses 2 major intracellular mediators
(InsP3 and DG), may induce normal dense granule
secretion in patients with impaired receptor-mediated secretion.
Platelet activation with a combination of ADP and either
1,2-dioctanoyl-sn-glycerol or A23187 improved secretion in 4
patients. However, a combination of
1,2-dioctanoyl-sn-glycerol and A23187 induced normal
secretion in platelet-rich plasma in all patients, suggesting that
the ultimate process of exocytosis or secretion per se is intact and
that impaired secretion in these patients results from abnormalities in
early signal transduction events.
There is growing evidence that protein phosphorylation
by tyrosine kinases (members of the Src-kinase family, the focal
adhesion kinase [FAK] family, pp72syk, and the
Janus [JAK] kinase family) plays an important role in platelet
signal transduction.37 In thrombasthenia38 39
and the Scott syndrome,40 tyrosine
phosphorylation of several proteins is impaired on
platelet activation. In these disorders, this defect is a result of
the primary abnormality in the GPIIb-IIIa complex and in phospholipid
scrambling, respectively.37 39 40
 |
Signal Transduction Defects and Activation of GPIIb-IIIa
Complex
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Activation of GPIIb-IIIa and platelet fibrinogen
binding, a
prerequisite for aggregation, is a signal
transductiondependent
process and has been linked to PKC activation.
Therefore, it
is likely that abnormalities in signaling mechanisms may
impair
the activation of GPIIb-IIIa on platelets. Evidence that
this
is indeed the case is provided by the decreased activation of
otherwise
normal platelet GPIIb-IIIa complexes in a patient with
markedly
abnormal platelet aggregation and impaired pleckstrin
phosphorylation.
41 The number and
ligand-binding capacity of the GPIIb-IIIa complex
were intact. A
similar abnormality in GPIIb-IIIa activation
has been observed in
platelets with the G
q
deficiency,
22 attesting
to the role of
G
q in GPIIb-IIIa activation. Moreover, the
defect
in GPIIb-IIIa activation provides a cogent explanation for
abnormalities
in initial aggregation responses noted by Lages and
Weiss
26 in a number of their patients. Diminished
activation of GPIIb-IIIa
secondary to upstream signal transduction
defects may be a more
common mechanism than defects in the GPIIb-IIIa
complex per
se in patients with blunted aggregation.
22
 |
Abnormalities in Arachidonic Acid Pathways and
Thromboxane Production
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A major platelet response to activation is liberation of
arachidonic
acid from phospholipids and its subsequent
oxygenation to TxA
2.
TxA
2 production plays a synergistic role
in the response to several
agonists. Patients have been described with
impaired liberation
of arachidonic acid from membrane
phospholipids during platelet
stimulation.
22 24 34
Several patients have been described with
platelet dysfunction
associated with congenital deficiencies
of
cyclooxygenase and thromboxane
synthase.
1
 |
Defects in Cytoskeletal Assembly
|
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The Wiskott-Aldrich syndrome (WAS) is an X-linked inherited
disorder
affecting T lymphocytes and platelets and characterized by
thrombocytopenia,
immunodeficiency, and eczema.
42 Several
platelet abnormalities,
including dense granule deficiency, have
been reported in WAS.
WAS arises from mutations in the gene coding for
a novel protein
of 502 amino acids that binds to several other
signaling proteins,
including Cdc42 (a GTPase) and p47nck (a Src
homology 3 domain
containing adapter protein).
42 43 This
protein constitutes
a link between the cytoskeleton and signaling
pathways and is
a key regulator of cytoskeletal
assembly.
43
 |
Relative Frequencies and Therapy of Various Platelet
Abnormalities
|
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Thrombasthenia and the Bernard-Soulier syndrome are rare
disorders.
Although there are no published data, patients currently
classified
in the heterogenous category of defects in
platelet secretion
and signal transduction probably constitute the
most frequently
encountered inherited platelet function
abnormalities, excluding
vWD. In our experience, the SPD is present
in <10% to 15%
of patients with congenital platelet defects.
Abnormalities
in thromboxane production occur in

20% of patients. A large
proportion of the remaining patients with
abnormal aggregation
and secretion demonstrate adequate dense granule
stores and
produce substantial amounts of TxA
2.
In some of these patients,
there is evidence for defects in the
signaling mechanisms. In
this heterogeneous group, the
underlying mechanisms still need
to be established. Platelet
transfusions have been the major
therapeutic modality to manage
bleeding in patients with intrinsic
platelet defects, and this
approach needs to be individualized.
A viable alternative is
intravenous administration of desmopressin
or
1-desamino-8-
D-arginine vasopressin (DDAVP), which shortens
the
bleeding time in a number of patients, particularly those with
normal
dense granule stores.
44 45 This response is
dependent on the
underlying mechanism leading to the platelet
dysfunction.
44 45
 |
Conclusions
|
|---|
There has been a tremendous advance in our understanding of
the
role of platelets in hemostasis, and part of this has resulted
from
characterization of the experiments of nature, such as
patients with
platelet function disorders. In the vast majority
of patients with
inherited platelet dysfunction, the underlying
mechanisms remain
unknown. A better delineation of the involved
platelet mechanisms
is required and will translate into development
of novel therapeutic
strategies for a diverse group of disordershemorrhagic,
thrombotic,
atherosclerotic, and proliferativein which
platelets are
involved.
 |
Acknowledgments
|
|---|
This work was supported by grant HL 056724 from the
National
Institutes of Health, National Heart, Lung, and Blood
Institute,
Bethesda, Md.
 |
Footnotes
|
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Reprint requests to A. Koneti Rao, MD, Division of Hematology
and Thromboembolic Diseases, Temple University Health Sciences
Center, Room 300 OMS, 3400 N Broad St, Philadelphia, PA 19140.
Received April 8, 1999;
accepted July 14, 1999.
 |
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