17

Platelets
FEDERICO DAZ-GONZLEZ
MARK H. GINSBERG

KEY POINTS
Platelets are small circulating cytoplasmic fragments that
play a crucial role in hemostasis.
Platelets release a variety of factors that contribute to
inflammation, including chemotactic factors for leukocytes;
factors that alter vascular tone and permeability; and
transforming growth factor-, a potent stimulus of
fibrosis.
Platelet surface proteins also participate in inflammation
by serving as sites for leukocyte adhesion (e.g.,
P-selectin, glycoprotein Ib [GPIb]) or as agonists for
counterreceptors on leukocytes (e.g., CD40 ligand,
platelet-activating factor).
Platelets have been implicated in the pathogenesis of several
rheumatic diseases, including rheumatoid arthritis and
systemic lupus erythematosus; in the latter case, they have
been particularly implicated in atherothrombotic
complications.
The development of antiplatelet agents offers the promise of
new therapeutic modalities.

Platelets are small circulating cytoplasmic fragments that

play a crucial role in hemostasis. They are produced in the
bone marrow by megakaryocytes. Single platelets circulate
freely in the bloodstream; after vascular injury, platelets
adhere to the subendothelium, resulting in responses that
contribute to formation of the hemostatic plug. These
responses include aggregation, secretion of bioactive compounds, and production of procoagulant activity. Platelets
also secrete soluble factors that contribute to wound repair
by altering vascular tone and permeability, promoting cell
growth, and stimulating scavenger cells such as monocytes.
During the inflammatory response, many of the activities
that lead to hemostasis contribute to inflammation.1 Inflammation initiates clotting, decreasing the activity of natural
anticoagulant mechanisms and impairing the fibrinolytic
system. Conversely, activated platelets release chemotactic
factors that promote leukocyte adhesion, which facilitates
their extravasation into inflammatory foci. Platelets secrete
a variety of factors that can alter vascular tone and permeability. Last, platelets are a major source of transforming
growth factor (TGF)-, a potent stimulus of fibrosis. Taken
together, these activities make platelets contributors to the
inflammatory response and to the pathogenesis of systemic
rheumatic diseases.2

GENERAL CHARACTERISTICS OF
PLATELETS
Platelets are the smallest blood cells; they are cytoplasmic
fragments derived from their bone marrow precursor, the
megakaryocyte. Resting platelets have a smooth disk shape
and are 3.6 0.7m in diameter. On activation, platelets
undergo a shape change, becoming a compact sphere with
numerous long dendritic extensions, markedly increasing
their surface area. In humans, normal platelet counts
range from 150,000/L to 450,000/L. The main function
of platelets is to maintain vascular integrity, thereby playing
a crucial role in hemostasis.
The plasma membrane of platelets is a typical lipid
bilayer, having an extensive series of complex invaginations
termed the canalicular system. The role of this surfaceconnected tubular system seems to be to facilitate the quick
release of secreted substances to the extracellular environment. The platelet membrane bears numerous glycoprotein
(GP) receptors. Platelet surface phospholipids play an
important role in coagulation3 and are a source of arachidonic acid, a precursor of important vasoactive substances
such as thromboxane A2, a potent vasoconstrictor and
platelet-aggregating agent, and of leukotrienes, which can
amplify the inflammatory response. Platelet surface GPs are
receptors that mediate adhesion to subendothelial tissue
and subsequent aggregation to form the hemostatic plug.4
The largest GP is termed I and the smallest IX. The labels
a and b distinguish between two separate electrophoretic
bands that initially were considered one (e.g., GPI became
GPIa and GPIb). The platelet GPIb-IX-V is an important
receptor that binds to von Willebrand factor (vWF) exposed
in the subendothelial matrix, causing the attachment of
platelets.5 Deficiency of any component of the GPIb-IX-V
complex or of vWF leads to the congenital bleeding disorders Bernard-Soulier disease (GPIb-IX-V complex)6 or von
Willebrand disease (vWD),7 respectively. vWF, in addition
to its important role in hemostasis, has been suggested to
promote inflammation, facilitating neutrophil diapedesis by
destabilization of the endothelial barrier.8
ADAMTS-13 (a disintegrin-like metalloprotease with
thrombospondin type I repeats 13) is a plasma protease that
cleaves vWF into smaller multimers, reducing its hemostatic potency.9 Mutations in the ADAMTS-13 gene10 and
autoantibodies against ADAMTS-1311 have been shown
to cause familial and acquired thrombotic thrombocytopenic purpura, respectively. In mice, ADAMTS-13 has powerful natural antithrombotic activity, and recombinant
ADAMTS-13 has proved useful in preventing ischemic
brain injury in experimental stroke.12 It has been suggested
that ADAMTS-13 might act as a link between thrombosis
and inflammation. In inflammatory models, ADAMTS-13
245

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has played an important role in preventing vWF-induced

secretion of Weibel-Palade bodies by endothelial cells and,
consequently, reducing the adhesion and extravasation of
leukocytes.13 Other interactions that contribute to initial
platelet adhesion are mediated by collagen receptors GPIaIIa (integrin 21) and GPVI, which bind to collagen in
the subendothelial matrix.14 The most abundant platelet
surface receptor, GPIIb-IIIa (integrin IIb3), is activated
by adhesion to collagen or vWF or by soluble agonists, such
as thrombin. After activation, GPIIb-IIIa binds fibrinogen,
leading to platelet aggregation.4 Deficiency of this GP
results in Glanzmanns thrombasthenia, a disorder characterized by petechial bleeding and the absence of platelet
aggregation and clot retraction.15
The cytoplasm of platelets is rich in actin and myosin,
which provide platelets the ability to change shape and to
retract clots. Platelet cytoplasm consists of mitochondria,
lysosomes, glycogen stores, and three types of granules that
contain numerous biologically active molecules (Table
17-1). These granules are classified according to their ultrastructure, density, and contents as alpha granules, lysosomes,
and dense granules. Although most of the contents of these
granules are made in megakaryocytes, some are taken up
from the plasma by megakaryocytes and platelets.
Alpha granules contain numerous proteins and growth
factors, such as platelet-derived growth factor (PDGF),
TGF-, platelet factor-4 (also referred to as CXCL4), and
vWF, which are synthesized in the megakaryocyte.16 Other
proteins, such as fibrinogen, enter the alpha granules from
the plasma via GPIIb-IIIa receptormediated endocytosis.17
P-selectin (CD62P), an adhesion molecule, also is localized
in the membrane of alpha granules18 and redistributes to the
cell surface during platelet activation. Platelet P-selectin
has been implicated in stabilizing platelet aggregates.19
The best documented high-affinity counterreceptor for
P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1), a
transmembrane sialomucin found on leukocytes and lymphoid cells,20 through whose interaction platelets participate in the inflammatory response.21
Dense granules contain serotonin, adenosine diphosphate (ADP), adenosine triphosphate, and calcium. The
dense granule membrane bodies are made in megakaryocytes, but they do not acquire their content of serotonin
and calcium until platelets are released into the circulation.22 Another series of intracellular membrane vesicles
serves as a reserve to increase membrane surface area on
platelet activation.

As stated previously, platelets are small cytoplasmic fragments derived from megakaryocytes. Although megakaryocytes are rare in the bone marrow (approximately 0.1% of
all nucleated cells), they are easily recognized by their giant
size (50 to 100m diameter) and large, multilobed nucleus.
Megakaryocytes have two unique characteristics: (1) They
undergo a process known as endomitosis, in which the
nucleus accumulates many times the normal number of
chromosomes, and (2) they have specialized structures in
the cytoplasm that permit fragments to be shed, as platelets,
into the bloodsteam.23
With a life span of just about 10 days, every day, about
2 1011 platelets are released into the bloodsteam of healthy
adults by mature megakaryocytes. This quantity can be
increased 10-fold under specific conditions. In humans, as
in other species, there is an inverse relationship between
platelet count and mean platelet volume.24 This suggests
that platelet production by bone marrow megakaryocytes is
regulated to maintain a constant total platelet mass. The
tendency toward a stable platelet mass explains the wide
variation in platelet count in healthy donors (150,000/L
to 450,000/L). Megakaryocytes normally replace about
10% of the platelet mass daily. In response to the increased
need for platelets, megakaryocytes modify their number,
size, and ploidy. Changes in free levels of thrombopoietin,
the main physiologic regulator of platelet production, are
responsible for these morphologic and functional adaptations in megakaryocytes.
Thrombopoietin is an 80- to 90-kD GP produced mainly
by the liver and released at a constant rate into the circulation. Thrombopoietin acts through its receptor, also known
as c-Mpl, which is present in platelets, megakaryocytes, and,
to a lesser extent, most other hematopoietic precursor cells.
Thrombopoietin prevents apoptosis of megakaryocytes,
while increasing their number, size, and maturation,25 but it
does not seem to increase the rate of shedding of platelets
into the circulation.26 On circulating platelets, thrombopoietin is not a sufficiently strong stimulus to trigger platelet
function, but it reduces the threshold for activation by
other agonists, such as ADP.27 Binding to the platelet
thrombopoietin receptor is the major route of catabolism,
however, of circulating thrombopoietin. When the platelet
production rate decreases, the platelet mass and the quantity of thrombopoietin receptor decrease; consequently,
thrombopoietin concentrations increase and megakaryocyte growth is stimulated. In conditions of high platelet
mass (e.g., hypertransfusion of platelets), the number of

Table 17-1 Platelet Granule Compounds and Granule Membrane Components with a Role in the Hemostatic/
Inflammatory Response
Platelet
Granules
Dense granule
Alpha granule

Lysosome

Actions

Contents

Proaggregating factors
Adhesive glycoproteins
Growth factors
Platelet aggregation and chemotaxis
Hemostasis factors
Tissue destruction

Serotonin, histamine, ADP, ATP, Ca2+, Mg2+

P-selectin, CD31, GPIIb-IIIa, fibronectin, vitronectin, thrombospondin
TGF-, PDGF, EGF, VEGF
-Thromboglobulin, PF4 (CXCL4), CC and CXC chemokines
Fibrinogen, vWF
Hydrolases, collagenase, cathepsins D and E

ADP, adenosine diphosphate; ATP, adenosine triphosphate; EGF, epidermal growth factor; GPIIb-IIIa, glycoprotein IIb-IIIa; PDGF, platelet-derived growth factor;
PF4, platelet factor-4; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor.
Modified from Rendu F, Brohard-Bohn B: The platelet release reaction: granules constituents, secretion and functions, Platelets 12:261, 2001.

CHAPTER 17

thrombopoietin receptors increases, thrombopoietin concentrations decrease, and megakaryocyte growth decreases.
In addition to thrombopoietin, other soluble factors, such
as interleukin (IL)-3, IL-6, IL-11, stem cell factor, or
granulocyte-macrophage colony-stimulating factor, seem to
promote megakaryocyte growth and maturation. Some of
these soluble proteins may play a relevant role in thrombocytosis conditions.28
Under normal conditions, the spleen stores about onethird of circulating platelets. Circumstances that increase
splenic volume, such as hepatic cirrhosis or portal hypertension, cause a reduction in the circulating platelet count by
a sequestration within the splenic sinusoids. Hypersplenism
does not reduce platelet life span, however; rather, it reduces
the circulating platelets available for effective hemostasis.
After senescence, platelets are removed from the circulation
by the reticuloendothelial system. Only a small fraction of
circulating platelets is consumed in forming hemostatic
plugs to maintain vascular integrity.

247

Platelets

P
F

P
EC
P
Figure 17-2 Anatomy of a platelet plug. Electron micrograph of a
group of platelets (P) attached to an endothelial cell (EC)120 in the initial
platelet plug formation. Several dense granules (d) and alpha granules
() are visible. The central platelet shows long dendritic extensions or
filopodia (F). (Courtesy Dr. Lucio Daz-Flores.)

FUNCTION OF PLATELETS
In response to vascular injury, platelets adhere to subendothelium, secreting a variety of potent agonists and aggregating to form a hemostatic plug. During the inflammatory
response, these physiologic responses of platelets can
promote and exacerbate inflammation. In this sense, platelets are authentic inflammatory cells.

HEMOSTASIS
When a blood vessel is injured, a complex process involving
biochemical reactions and cell-cell and cell-matrix interactions, termed hemostasis, occurs. The initial hemostatic
response is mediated by platelets that form the platelet plug
(Figure 17-1).

Amplification

Adhesion

Aggregation

Secretion

Exposure of
subendothelial
matrix
Figure 17-1 Platelet plug formation. Platelet activation can be initiated
by several mechanical (vessel wall injury, disruption of atherosclerotic
plaques) or chemical (adenosine diphosphate, epinephrine, thromboxane A2, and thrombin) stimuli. In response to vessel wall injury, platelets
attach to subendothelial matrix (adhesion); this is followed by fibrinogenmediated platelet-platelet interaction (aggregation). Simultaneously,
platelets release their intracellular granule contents (secretion), leading
to recruitment of additional circulating platelets (amplification).

Under physiologic conditions, the undamaged endo

thelium prevents the adherence of platelets by several
mechanisms. These mechanisms include a cell-associated
ecto-ADPase (CD39) and the production of nitric oxide
and prostacyclin.29 When blood vessel integrity is disrupted,
the first reaction is vasoconstriction, which reduces blood
loss. Simultaneously, subendothelial matrix elements are
exposed, and platelets are rapidly transformed into sticky
cellular elements capable of adhering to the underlying
surface. Platelet adhesion is initially mediated by the interaction of the GPIb-IX-V receptor complex with vWF in the
subendothelial matrix.5 This interaction transduces signals
through the GPIb-IX-V complex that activate platelet integrins.30 The activation of GPIa-IIa and GPIIb-IIIa integrins
allows the binding to collagen (GPIa-IIa) and vWF (GPIIbIIIa), mediating the stable adhesion of platelets to the subendothelial surface. In addition to vWF, the active form of
GPIIb-IIIa binds fibrinogen.31 The association of soluble
fibrinogen with GPIIb-IIIa creates bridges between platelets
that result in platelet aggregation and thrombus growth. In
concert with aggregation, platelets release their intracellular
granules, amplifying the hemostatic response (see Table
17-1).32,33 The outcome is the formation of a platelet plug
and triggering of the coagulation cascade, which leads to
thrombin generation and resulting fibrin clot formation
(Figure 17-2).
One response of platelets to activation by stimuli such
as shear stress or collagen is the release of vesicles called
platelet microparticles, fragments 0.1 to 0.2m in diameter
that carry antigens present in intact platelets. These
platelet-derived microparticles may play a role in normal
hemostasis.34,35 The number of clinical disorders associated
with elevated platelet microparticles is increasing,36,37
including several rheumatic diseases in which the number
of circulating platelet microparticles seems to be associated
with disease activity.38-41 The relevance of platelet-derived
microparticles in the physiopathology of those disorders
needs to be fully clarified; however, it has been demonstrated that platelets intensify the inflammatory response in
joint42 (Figure 17-3).

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90
Platelet depletion
Control IgG

ankle thickness (0.01 mm)

80
70
60
50
40
30
20
10
0
0

Days

Figure 17-3 Platelets can be involved in the development of arthritis.

The passive K/BxN model of arthritis is induced by administration of
arthritogenic serum containing antibodies to glucose-6-phosphate
isomerase (GPI). The graph shows arthritis severity after K/BxN serum
transfer in mice administered a platelet-depleting antibody (red squares)
or isotype control (blue squares). Data show the mean standard error
of the mean (SEM).42 Arrows indicate parenteral administration of
platelet-depleting antibody; arrowhead, K/BxN serum administration.
These findings suggest that platelets are required for arthritis development in vivo in this model.

GLYCOPROTEIN IIB-IIIA
GPIIb-IIIa is a member of a family of cell-adhesion receptors
termed integrins. It also is referred to as integrin IIb3 or
CD41/CD61. Although integrins are expressed on virtually
all nucleated cells, GPIIb-IIIa is restricted to megakaryocytes and platelets. It is the most abundant receptor on the
platelet surface, averaging 80,000 copies per platelet. GPIIbIIIa recognizes at least five different adhesive ligands43: fibronectin, fibrinogen, vWF, thrombospondin, and vitronectin.
Cells can modify integrin functions through dynamic modulation of receptor affinity.43 On resting platelets, GPIIb-IIIa
does not bind soluble fibrinogen. After platelet stimulation
(e.g., by thrombin, collagen, or ADP), GPIIb-IIIa undergoes
a conformational change, however, and is converted from a
low-affinity to a high-affinity fibrinogen receptor, a process

known as inside-out signaling. In this situation, fibrinogen

bridges the activated platelets, and platelet aggregation
occurs. Simultaneously, the cytosolic portion of the activated GPIIb-IIIa binds to platelet cytoskeleton proteins and
mediates platelet spreading and clot retraction in what is
referred to as outside-in integrin signaling. GPIIb-IIIa integrates receptor-ligand interactions on the external face of
the membrane with cytosolic events in a bidirectional
fashion.4 This is the final common pathway for platelet
aggregation, regardless of the mode of platelet stimulation.
The importance of GPIIb-IIIa integrin is illustrated by
Glanzmanns thrombasthenia, a bleeding disorder caused
by mutations in the gene for the IIb- or the 3-subunit,15
and by the clinical utility of GPIIb-IIIa antagonists as
antithrombotic agents in the treatment of thrombotic diseases. Glycoprotein IIb-IIIa inhibitors are now recommended by international guidelines in patients with acute
coronary syndromes undergoing percutaneous coronary
intervention.

ROLE OF PLATELETS IN THE

INFLAMMATORY RESPONSE
The accumulation of leukocytes in tissue is an essential
event for the inflammatory response. The current paradigm
of leukocyte extravasation requires a multistep cascade of
sequential leukocyteendothelial cell interactions, in which
members of three different families of adhesion receptors
participate: selectins, integrins, and the immunoglobulin
superfamily.44 Platelets contribute in many ways to leukocyte accumulation in the inflammatory foci (Table 17-2).
In flowing blood, leukocytes roll on adherent activated
platelets, mainly through the interaction of platelet
P-selectin with its major leukocyte ligand, PSGL-1.45 This
initial rolling of leukocytes on platelet P-selectin is followed
by their firm adhesion and subsequent migrationprocesses
that depend on the leukocyte integrin Mac-1 (M2,
CD11b/CD18).45,46 Mac-1 adheres firmly to platelets
through direct binding to glycoprotein Ib (GPIb,
CD42b).47 These interactions provide molecular mechanisms for leukocyte recruitment to hemostatic plugs where
platelets have been previously deposited in response to vascular injury.48 Parallel lines of investigation have shown that
resting platelets are able to roll on activated endothelial
cells, apparently through an interaction between PSGL-1
expressed in platelets and the endothelial P-selectin.49 The

Table 17-2 Platelet Components Implicated in the Inflammatory Response

Surface molecules
Soluble factors

End products of platelet procoagulant activity

Platelet Component

Actions

P-selectin (CD62P), PECAM (CD31), GPIb

PAF, ROS
CD154 (CD40 ligand)
Serotonin, histamine
-Thromboglobulin, PF4
Acid hydrolases, ROS
PDGF, TGF-
Thrombin, fibrin

Adhesive targets for leukocytes

Neutrophil activation
Agonist for endothelial cells
Regulators of vascular permeability
Chemotaxis
Tissue destruction
Cellular mitogens, chemoattractant
Promote leukocyte accumulation

GPI, glycosyl phosphatidylinositol; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PECAM, plateletendothelial cell adhesion molecule;
PF4, platelet factor-4; ROS, reactive oxygen species; TGF, transforming growth factor.

CHAPTER 17

physiologic function of platelet rolling on stimulated endothelial cells needs to be clarified. If this contact results in
activation of platelets, however, those platelets may release
proinflammatory mediators, such as cytokines, chemokines,50,51 and eicosanoid precursors,52 or growth factors that
stimulate tissue healing. Activated platelets in circulation
stimulate secretion of Weibel-Palade bodies from endothelial cells in vivo; this leads to P-selectinmediated leukocyte
rolling.53 Given the important role of platelet P-selectin in
chronic inflammatory processes,54,55 this effect of activated
platelets might represent an important pathway of plateletinduced inflammation.
In addition to the adhesion molecules, activated platelets express on their surface two major proinflammatory
mediators: platelet-activating factor (PAF) and CD40
ligand (CD154). PAF is a potent platelet-aggregating phospholipid produced by macrophages, mast cells, platelets,
endothelial cells, neutrophils, and monocytes. Upon cell
activation, PAF is rapidly synthesized and translocated to
the plasma membrane of endothelial cells, where it recognizes its receptor in neutrophils, resulting in 2 integrin
mediated adhesion of leukocytes to the endothelial surface.56
In the same way, PAF can signal neutrophils when it is
displayed on the surface of adherent activated platelets
acting in cooperation with P-selectin to tether neutrophils.56 The biologic action of PAF is physiologically inactivated by plasma and cellular acetylhydrolase.57 A role of
PAF in the pathogenesis of chronic inflammatory arthritis
has been proposed58; however, a well-controlled clinical
trial failed to show any beneficial effect of a PAF antagonist
in patients with active rheumatoid arthritis (RA).59
CD40 is a transmembrane protein member of the tumor
necrosis factor (TNF) receptor family. CD40 is present on
many cells, including B cells, monocytes, macrophages,
dendritic cells, and vascular endothelial cells. Platelets are
the major peripheral blood source of CD154, the ligand of
CD40, and they express it on their surface within seconds
of exposure to an agonist. The interaction of CD154 on
activated platelets with CD40 on endothelial cells causes a
proinflammatory reaction of the endothelium characterized
by expression of inflammatory adhesion molecules, such as
E-selectin, vascular cell adhesion molecule-1 (CD106), and
intercellular adhesion molecule-1 (CD54), and secretion of
the chemokines IL-8 (CXCL8) and monocyte chemotactic
protein-1 (CCL2).60 CD154 expressed on activated platelets can provide a potent stimulus to the inflammatory
response. Clinical data from an open-label study suggested
that the blockade of CD154 with a biologic may induce a
prothrombotic state in patients with lupus nephritis through
a mechanism not clarified.61 A phase II, double-blind,
placebo-controlled study evaluating the safety and efficacy
of a humanized monoclonal antibody against CD154 in
patients with active systemic lupus erythematosus failed to
show clinical efficacy. In this study, the type and frequency
of adverse events were similar between the intervention and
placebo groups.62
When platelets adhere, they release numerous growth
factors, such as PDGF, TGF-, and other factors that
are chemotactic for monocytes, macrophages, and fibroblasts. These growth factors may play an important role in
the chronic inflammatory response by mediating a

Platelets

249

fibroproliferative response. PDGF is a homodimer or heterodimer molecule of A and B chains63 produced by platelets, monocytes or macrophages, endothelial cells, and
vascular smooth muscle cells (under some conditions). This
molecule plays an essential role in tissue repair and wound
healing.64 PDGF is a potent mitogen and chemoattractant
for smooth muscle cells, connective tissue cells, and
macrophages65-68; it contributes to the formation of lesions
of atherosclerosis,68,69 a disorder strongly related to the
inflammatory response.70 It has been shown that PDGF is a
potent mitogen for synovial fibroblasts isolated from patients
with RA.71
TGF- has three isoforms (TGF-1, TGF-2, and TGF3) secreted by virtually all cell types as latent complexes
that need to be processed to exhibit biologic activity.72
Several effects have been associated with TGF-: (1) It is
chemotactic for various cell types, including leukocytes; (2)
it inhibits proliferation of most cells; (3) it induces the
synthesis and deposition of extracellular matrix; and (4) it
stimulates the formation of granulation tissue.73 The net
result is that TGF- is mainly an inhibitor of the inflammatory response.74 Carefully regulated expression of active
TGF- is essential for resolution of inflammation and repair.
Systemic administration of TGF-1 has antagonized the
development of polyarthritis in susceptible rats.75 Overproduction of this cytokine has been associated with several
fibrotic processes.76,77 TGF- is a major cytokine involved
in the pathogenesis of fibrosis in systemic sclerosis.78 Blockade of cell surface molecules capable of activating latent
TGF- and blockade of ligand by antibody, soluble TGF-
receptors, and a recombinant latency-associated peptide, as
well as inhibitors for ALK5 and Smad3, are potential strategies for abolishing the pathologic activation of TGF- in
systemic sclerosis.
Several reactive oxygen species are released from unstimulated platelets and after platelet stimulation with agonists
such as collagen or thrombin.79,80 Because reactive oxygen
species have been implicated in direct tissue injury and in
inflammatory reactions through promotion of adhesive
interactions between inflammatory and endothelial cells,81
reactive oxygen species originating from platelets may act
as an autocrine or paracrine mediator that participates in
the amplification of the inflammatory response in disorders
such as rheumatic diseases.

PLATELETS AND RHEUMATIC DISEASES

Alterations in Platelet Numbers
in Rheumatic Diseases
Increases in platelet counts have three major causes: (1)
reactive or secondary thrombocytosis; (2) familial thrombocytosis; and (3) clonal thrombocytosis, including essential
thrombocythemia and related myeloproliferative disorders.
The platelet count is frequently elevated in patients with
active RA and juvenile chronic arthritis, owing to reactive
thrombocytosis. The level of thrombocytosis correlates with
clinical and laboratory parameters of disease activity.
Relapses of RA are often accompanied by increases in platelet count, whereas remissions are associated with their
reduction, to normal limits.82 This activity indicates that

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the thrombocytosis observed in patients with rheumatic

disease is reactive or occurs secondary to the chronic inflammatory process. Although the mechanism responsible for
thrombocytosis is uncertain, increased intravascular coagulation with a compensatory increase in platelet production
has been suggested as a possible cause.83 More recently,
several studies suggested that inflammatory cytokines with
a minor role in the physiologic production of platelets, such
as IL-6, IL-1, or TNF, among others,84,85 may be active mediators in the regulation of thrombopoiesis during the reactive
thrombocytosis that occurs in the inflammatory process.
Reduced platelet count, or thrombocytopenia, is common
in rheumatic diseases. The mechanisms involved in thrombocytopenic states include reduction in platelet production,
sequestration, and rapid platelet destruction. Several drugs
used in rheumatic diseases are able to suppress the bone
marrow. Among drugs that can produce thrombocytopenia
because of megakaryocytic hypoplasia are gold, cyclophosphamide, methotrexate, penicillamine, and azathioprine.
The effect these compounds have on suppressing megakaryocyte replication depends on the time and dose of exposure; reduced elimination of these drugs places patients at
increased risk for this complication.86
The normal spleen contains about 30% of the platelet
mass, and splenomegaly can result in a low circulating count
without reduction in the platelet life span.87 Several rheumatic diseases may lead to this type of thrombocytopenia.
The best known is Feltys syndrome, an uncommon but
severe subset of seropositive RA complicated by granulocytopenia and splenomegaly. In this disorder, thrombocytopenia usually is not life threatening.
Another related disease is immune-mediated platelet
destruction,88 a disorder termed idiopathic thrombocytopenic
purpura. Autoantibodies cause idiopathic thrombocytopenic purpura, and platelet surface proteins, including GPIIbIIIa, GPIb-IX, GPIa-IIa, GPV, and GPVI, can be antigenic
targets of such autoantibodies.89,90 Circulating platelets
coated with immunoglobulin (Ig)G autoantibodies undergo
accelerated clearance through Fc receptors expressed by
macrophages in the spleen and liver. In some cases of idiopathic thrombocytopenic purpura, platelet production
seems to be reduced, either by intramedullary destruction of
antibody-coated platelets or by inhibition of megakaryocytopoiesis.91 The level of thrombopoietin is not increased,92
suggesting a normal megakaryocyte mass. Idiopathic thrombocytopenic purpura is present in 15% to 25% of patients
with systemic lupus erythematosus93 and in about 25% of
patients with antiphospholipid syndrome.94
In contrast, the thrombocytopenia that occurs during
episodes of systemic vasculitis has a more complex pathogenesis, a worse clinical course, and a poorer outcome.95,96
Immune thrombocytopenia is rare in RA except when
related to therapy. Among the drugs that can produce
thrombocytopenia in RA, intramuscular gold salts are
the most clearly associated with drug-induced immune
thrombocytopenia. About 1% to 3% of patients receiving
intramuscular gold salts for the treatment of RA develop
a thrombocytopenia, which may be life-threatening.
Although, as stated previously, bone marrow suppression
can occur in patients undergoing gold treatment, thrombocytopenia is usually due to immune destruction of platelets
associated with an active marrow.97

Role of Platelets in the Pathogenesis of

Rheumatic Diseases
The role that platelets play in amplification of the inflammatory response provides a basis for their involvement
in rheumatic diseases. Most of the available evidence implicating platelets in the pathogenesis of rheumatic disorders
is indirect and circumstantial; however, current findings
based on pharmacologic and genetic experimental procedures demonstrate a previously unappreciated role for
platelet microparticles in the pathogenesis of rheumatic
diseases.42
Platelets have been implicated in the pathogenesis of
RA2,98 on the basis of several studies that have documented
the presence of platelet proteins in the synovial fluid of RA
patients99 and on the observation that labeled platelets
localize only to joints with clinically active inflammation.100
Levels of plasma-soluble P-selectin are increased in RA
patients compared with controls,101 indicating platelet activation in this disease. A direct correlation has been observed
between platelet-derived microparticle levels and disease
activity in RA patients; this suggests that generation of
platelet microparticles38,41 contributes to the pathogenesis
of RA. Microparticles are abundant in RA, psoriatic arthritis, and juvenile idiopathic arthritis synovial fluid both in
suspension and adhered to the surface of leukocytes. Solid
evidence supports that platelet microparticles are generated
by platelet activation via the collagen receptor GPVI,
locally in the synovial tissue. Once in the joint, microparticles seem to play a proinflammatory role, exerting potent
IL-1mediated activation of resident synoviocytes42 (Figure
17-4). These findings support platelet GPVI as a potential
target for arthritis treatment.
Several studies have focused on the presence of activated
platelets in patients with systemic lupus erythematosus.102-104
The risk for thrombosis is increased significantly in these
patients, and platelets have been implicated in the prothrombotic state of systemic lupus erythematosus through
the release of microparticles40 and by the increased deposition of complement activation product C4d on the platelet
surface.105,106 Patients with essential thrombocythemia have
an increased prevalence of antiphospholipid antibodies,
which may be associated with a higher risk of thrombosis.107
The presence of activated platelets and enhanced aggre
gation of platelets have been described in patients with
antiphospholipid syndrome,103 systemic sclerosis,108,109
primary Raynauds phenomenon108 and ankylosing
spondylitis.110

INHIBITION OF PLATELET FUNCTION BY

PHARMACOLOGIC AGENTS
Nonsteroidal anti-inflammatory drugs (NSAIDs) serve as
the foundation of therapy in many rheumatic diseases.
NSAIDs inhibit prostaglandin synthesis111 through blockade of cyclooxygenase (COX). These agents can interfere
with platelet aggregation and secretion112,113 through the
inactivation of platelet COX-1. In platelets, this enzyme is
a rate-limiting step in the transformation of arachidonic
acid into thromboxane A2, a potent platelet-aggregating
agent. In addition, some NSAIDs reduce platelet

CHAPTER 17

Platelets

251

Circulating
platelets
Endothelial cells
Basal membrane
(type IV collagen)
Generation of
platelet
microparticles
(MPs)

Synoviocytes

IL-1 activity

MP

IL receptor

Activation

Figure 17-4 Model of how platelet microparticle (MP) generation might contribute to joint inflammation.42 Circulating platelets make contact with
extracellular matrix collagen type IV of fenestrated subsynovial capillaries. This contact generates platelet MPs, which once in the synovial membrane
activate resident synoviocytes through potent interleukin (IL)-1 activity.

aggregation by interfering with the activation of GPIIb-IIIa

through a COX-independent mechanism.114 NSAIDs
inhibit platelet function and can lead to bleeding complications in patients with rheumatic diseases.
Newly developed potent antithrombotic agents also
might provide new weapons in the treatment of rheumatic
diseases. Among these are ticlopidine and its analogue,
clopidogreltwo inhibitors of the P2Y12 ADP receptor.
Nowadays, many other members of this family of antiplatelet agents are being tested for control of procoagulant
states.115 These agents have greater efficacy than aspirin for
the prevention of recurrent stroke116 and may find a place
in the antirheumatic armamentarium as a result of their
potential anti-inflammatory properties.117,118 However, no
information is available about clinical trials specifically
designed to test the effect of P2Y12 inhibitors in the control
of rheumatic diseases. Agents that interfere directly with
the adhesive function of integrin GPIIb-IIIa have come into
therapeutic use. This new group of agents includes monoclonal antibodies (abciximab), cyclic peptides (eptifibatide), and other small molecules that have been approved
for intravenous coronary angioplasty and stent procedures.
Orally active GPIIb-IIIa blockers have been developed for
long-term therapy, including secondary and even primary
prevention of thrombotic diseases. However, available data
from clinical trials of these oral agents have failed to show
clinical benefit, whereas they have shown unexplained
increased mortality.119
Acknowledgments
This work was supported by grants from the National Institutes of Health
(NIH) and from the Instituto de Salud Carlos III of Spain (FIS09/02209).
We are indebted to Dra. Esmeralda Delgado-Frias for the artwork.

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