Platelets
WB Mitchell, Laboratory of Platelet Biology, New York Blood Center, New York, NY, USA
2014 Elsevier Inc. All rights reserved.
Glossary
Granules The vesicles within platelets that contain the
>300 different substances released upon platelet
activation. The a-granules are the smallest and most
numerous, while the dense granules are larger.
Hemostasis The process that causes bleeding to stop,
which depends on cooperative functioning of the blood
vessel, the platelets, and the plasma clotting factors.
Platelet aggregation The clumping together of platelets
either in the blood for hemostasis, or as part of a diagnostic
test.
Platelets
Platelets are tiny anucleate cells in the blood that play a crucial
role in maintaining hemostasis by mediate blood clotting at
the sites of blood vessel damage. Platelets also participate in
inammation, angiogenesis, innate immunity, and other
nonhemostatic physiologic processes. Platelets are the smallest
of blood cells, measuring only 25 mm in diameter. About
1 trillion platelets circulate in an average persons bloodstream,
and the turnover is such that the entire platelet population is
replaced every 10 days. While normally quiescent, upon acti-
vation platelets undergo a drastic shape change, become highly
adhesive, and secrete more than 300 different proteins and
chemicals. Many diseases and their treatments cause throm-
bocytopenia or platelet dysfunction, which can lead to life-
threatening bleeding. Additionally, platelets contribute to the
pathophysiology of venous thromboembolism, atheroscle-
rosis, tumor metastasis, and other pathologic conditions.
Platelets and their functions are important in medicine:
transfusion of platelets is lifesaving to a thrombocytopenic
patient, while antiplatelet drugs can prevent death after stroke
and myocardial infarction. Accordingly, much biomedical
research is focused on either improving our ability to increase
platelet counts, or on generating safer antiplatelet agents.
Transfusion of donated platelets is the mainstay of increasing
platelet counts, although other modalities are available to
increase platelet function or number. Antiplatelet drugs are
generally targeted to one of the activation pathways that are
critical for normal platelet function. As the role of platelets in
nonhemostatic processes is further dened, it is likely that future
platelet-related therapies will also be targeted to those processes.
Platelet Structure
Platelets circulate in the blood in an inactive, quiescent state so
as not to initiate blood clotting in the wrong place. Quiescent
platelets are discoid in shape due to the presence of
Reference Module in Biomedical Research, 3rd edition http://dx.doi.org/10.1016/B978-0-12-801238-3.00062-3
Thrombocytopenia The state of having a low platelet
count, generally below 150 000 ml 1 of blood.
Venous thromboembolism A blood clot within a vein that
can break off (embolize) and travel to the lungs, causing
further clotting. A clot within the large vein is a deep vein
thrombosis (DVT): a clot within the lungs is a pulmonary
embolism (PE).
a microtubule ring around the cell periphery (Figure 1). They
are coated with surface proteins through which they interact
with the vessel wall, other blood cells, and substances in the
blood plasma. The most densely arrayed surface adhesion
receptor, aIIbb3, is present in an inactive, nonadhesive confor-
mation, which prevents platelets from binding to surfaces until
signaled to do so. The other major adhesive surface protein is
GPIb-IX-V, which is responsible for initiating platelet interac-
tion with the blood vessel wall endothelium at the sites of
injury. Inside the platelets are storage vesicles, or granules,
which house all of the protein and chemical contents that will
be released upon activation. The small a-granules are the most
numerous granules, while the dense granules are larger and less
numerous. Both types of granules contain numerous and
distinct proteins and chemicals. The platelet ultrastructure is
riddled with interconnected membrane tunnels that are also
connected to the surface. These structures constitute the open
canalicular system and are thought to increase the rapidity of
granule release (George, 2000).
Platelets in Blood Clotting
Blood clot formation typically progresses through three phases:
initiation, extension, and stabilization (Figure 2). When given
the appropriate signals, usually by damaged blood vessel walls,
platelets undergo activation and initiate formation of a blood
clot. Platelets initiate blood clotting by tethering to and literally
rolling on damaged endothelial cells at sides of blood vessel
injury. This interaction is mediated by von Willebrand factor
and collagen that are exposed on the damaged vessel wall
binding to GPIb-IX-V on the platelet surface. If this binding is
strong enough the platelets will sit down and spread onto the
injured surface and form a monolayer of adhesive platelets
(Brass, 2010).
Extension occurs when the rst layer of platelets become
activated and releases substances that attract and activate other
platelets. The most potent of these are thrombin, ADP, and
1
2 Platelets

Figure 1 Platelet structure. Top panels show scanning EM images of a quiescent (left) and an activated platelet. Bottom panels show transmission
EM images of a quiescent (left) and an activated platelet. The illustration on the left identies the ultrastructural features of the resting platelet.
Adapted from George, J.N., 2000. Platelets. Lancet 355 (9214), 15311539, with permission. Elsevier.

Figure 2 Platelet function in thrombosis. (a) Blood vessel walls help keep platelets quiescent by expressing CD39, prostaglandin (PGI2), and
nitrous oxide (NO). Vessel wall injury exposes von Willebrand factor and collagen, which attract platelets. (b) Platelets roll onto the exposed sub-
endothelium, form a monolayer, and become activated. (c) The initial layer of platelets activates, releasing ADP, thrombin, and thromboxane (TxA2),
which induce activation and recruitment of other platelets. (d) These platelets crosslink with brinogen and support further thrombin generation on
their surface. The clot is stabilized by further crosslinking by factor XIII.
 Platelets 3

thromboxane-A2. ADP is secreted from the platelet dense Table 1 Partial list of molecules secreted from platelets
granules, thromboxane-A2 is generated from the lipids of the
activated platelet membrane, and thrombin is generated by the a-Granules Dense granules
plasma coagulation proteins on the surface of the activated Platelet-specic proteins ADP
platelets. This second wave of platelets binds to the rst Platelet factor 4 ATP
monolayer and extends the clot outward from the vessel wall. b-Thromboglobulin familya Calcium
This results in further release of procoagulant substances and Multimerin Serotonin
activation of the platelet surface protein aIIbb3. Upon activa- Adhesive glycoproteins Pyrophosphate
tion, the aIIbb3 surface receptor undergoes a conformational Fibrinogen GDP
change into an active, highly adhesive form that can bind von Willebrand factor Magnesium
von Willebrand factor Other secreted or released proteins
brinogen, von Willebrand factor, and other large proteins in
propeptide
the plasma. These proteins are large enough to reach from
Fibronectin Protease nexin I
platelet to platelet, which leads to crosslinking and extension of Thrombospondin-1 Gas6
the clot in three dimensions. Simultaneously, the thrombin Vitronectin Amyloid b-protein precursor
activated by the coagulation factors generates a brin mesh that (protease nexin II)
binds the thrombus together. Finally, factor XIII, which is also Coagulation factors Tissue factor pathway inhibitor
secreted by activated platelets, crosslinks the brin mesh, Factor V Factor XIII
solidifying the clot. Protein S a1-Protease inhibitor
Factor XI Complement l inhibitor
Mitogenic factors High molecular weight kininogen
Platelet-derived growth factor a2-Macroglobulin
Platelet Secretion
Transforming growth Vascular permeability factor
factor-b
Platelets contain two main types of storage granules that release Endothelial cell growth Interleukin-1b
their contents upon platelet activation: a-granules and dense factor
granules. Together they secrete more than 300 substances upon Epidermal growth factor Histidine-rich glycoprotein
platelet activation. A partial list is in Table 1 (Smyth et al., Insulin-like growth factor I Chemokines
2009). Although many of these substances are procoagulant Angiogenic factors MIP-Ia (CCL3)
molecules, such as ADP and brinogen, many others have Vascular endothelial RANTES (CCL5)
diverse functions such as inammation and angiogenesis. growth factor
These functions beyond hemostasis are discussed below. Platelet factor 4 (inhibitor) MCP-3 (CCL7)
Fibrinolytic inhibitors Gro-a (CXCL1)
a2-Plasmin inhibitor Platelet factor 4 (CXCL4)
Plasminogen activator ENA-78 (CXCL5)
Life of a Platelet inhibitor-1
Albumin NAP-2 (CXCL7)
Platelets are born in the bone marrow and live only 710 days Immunoglobulins Interleukin-8 (CXCL8)
in circulation. This means that the parent cells of the platelets, Granule membrane-specic TARC (CCL17)
the megakaryocytes, must produce about 100 billion platelets proteins
a day. Megakaryocytes are huge cells that reside in the bone P-selectin (CD62P)
marrow. They become so large by undergoing endor- CD63 (LAMP-3)
eduplication, a process in which the cell duplicates its nucleus GMP 33
and cell contents but does not divide. Megakaryocytes can CCL, CC motif ligand; CXCL, CXC motif ligand; ENA, epithelial cell-derived
attain more than 128 times the normal cellular and nuclear neutrophil-activating (peptide); GMP, granule membrane protein; Gro, growth-
contents. All of this material is needed to manufacture the related oncogene; LAMP, lysosome-associated membrane protein; MCP, mono-
cyte chemoattractant protein; MIP, macrophage inammatory protein; NAP,
20005000 platelets that each megakaryocyte produces. At the neutrophil-activating peptide; RANTES, regulated on activation, normal T-cell
end of its life the megakaryocyte undergoes controlled frag- expressed and secreted; TARC, thymus and activation-regulated chemokine.
a
mentation of its entire contents into platelets. These fragments Platelet basic protein, low-afnity platelet factor 4, b-thromboglobulin, and
b-thromboglobulin-F.
are released into the bloodstream and platelets are born Adapted from Smyth, S.S., McEver, R.P., Weyrich, A.S., et al., 2009. Platelet
(Hartwig and Italiano, 2003). functions beyond hemostasis. J. Thromb. Haemost. November 7 (11), 17591766,
with permission. 2009 International Society on Thrombosis and Haemostasis.
Normal platelets will circulate in the bloodstream for up to
10 days if not recruited to a blood clot. The spleen is a large
organ in the abdomen that essentially lters the blood and Upon stress, such as infection, the cell may activate the pro-
removes old or damaged cells. About 25% of circulating apoptotic proteins and undergo programed cell death. Platelets
platelets are trapped inside the spleen at any given time. These also contain pro- and antiapoptotic proteins. However, since
platelets are not destroyed, however, and may be released platelets do not have a nucleus, they are packaged at formation
from the spleen and resume circulation. Platelet lifespan is with a relatively xed amount of these proteins, which degrade
controlled by programed cell death, or apoptosis, in which over time. Thus, once the antiapoptotic proteins, primarily
a cell triggers its own death and degradation. All cells, including Bcl-xl, degrade to a certain point the proapoptotic proteins will
platelets, contain a mixture of pro- and antiapoptotic proteins. trigger programed cell death. It has been demonstrated in mice
During normal cell life, the antiapoptotic proteins keep the that the platelet level of Bcl-xl directly determines the platelet
proapoptotic proteins in check and the cell lives a normal life. lifespan (Josefsson et al., 2012).
4 Platelets
Platelets in Medicine
Thrombocytopenia
Bleeding and clotting are delicately balanced: disrupting this
balance causes serious medical conditions. Low platelets, or
thrombocytopenia, can result in serious or life-threatening
bleeding. The normal platelet count in blood is above
150 000 platelets per microliter, and averages about
300 000 ml 1. The risk for bleeding from minor trauma
increases when platelet counts drop below 80 000 ml 1, and
spontaneous bleeding occurs below 10 000 ml 1. These very
low counts can result from malignancy and from the chemo-
therapy used to treat it, diseases of the immune system, massive
trauma, and severe illness. The primary treatment for severe
thrombocytopenia is platelet transfusion. In the United States
about 12 million platelet transfusions are given every year.
Each of these units of platelets is collected from volunteer
donors who are rigorously screened for any blood-borne
infection. There are three major causes of thrombocytopenia:
decreased production, increased destruction, and abnormal
distribution. Abnormal distribution occurs when the fraction
of sequestered platelets in the spleen rises dramatically, leading
to clinically signicant thrombocytopenia. This typically occurs
in the setting of splenomegaly, such as in leukemia,
lymphoma, viral infection, or portal hypertension.
Acute onset of decreased production of platelets most
commonly occurs due to hematological malignancy, such as
leukemia, or its treatment with chemotherapy. Bleeding from
the mucus membranes and diffuse bruising are the most
common presenting symptoms of severe thrombocytopenia.
Bone marrow examination will reveal decreased numbers of
megakaryocytes. Patients receiving chemotherapy or radiation
therapy for cancer treatment will have predictable thrombocy-
topenia. Infectious diseases, including viral, bacterial, fungal and
mycobacterial, may also cause bone marrow suppression and
thrombocytopenia. Several drugs are known to reduce platelet
production, notably valproic acid and mammalian target of
rapamycin inhibitors. Chronic exposure to benzene or other
toxins can also cause bone marrow failure. Liver failure results in
decreased production of thrombopoietin, which can result in
lower megakaryocyte production and thrombocytopenia.
Decreased platelet survival is a common cause of throm-
bocytopenia in severely ill patients. Platelets are used normally
or destroyed abnormally faster than the marrow can produce
them. If the marrow is healthy and trying to compensate,
a review of the peripheral blood smear or the mean platelet
volume will reveal large platelets, consistent with increased
numbers of larger immature platelets and stress thrombopoi-
esis. In general, critically ill patients tend to have higher platelet
turnover, particularly in the setting of fever, sepsis, and
bleeding. The rapid platelet turnover may be from increased
utilization for hemostasis or from nonfunctional destruction. It
is useful to divide platelet destruction into immune and
nonimmune mediated. Immune-mediated thrombocytopenia
is generally of two types: immune thrombocytopenia (ITP) and
drug-induced thrombocytopenia. Both will be discussed below.
Immune Thrombocytopenia
ITP is a frequent cause of severe thrombocytopenia platelet
count <20 000 ml 1. Despite the severity of the
thrombocytopenia and bleeding risk, the majority of patients
do not have serious bleeding. However, some ITP patients
become profoundly thrombocytopenic with severe mucocuta-
neous, gastrointestinal, or intracranial bleeding. In ITP the
platelets are coated with autoantibodies and are cleared from
the circulation by macrophages in the spleen and liver.
In addition the autoantibodies interfere with platelet produc-
tion in the bone marrow, resulting in both increased destruc-
tion and decreased production. Therapies are directed at
both reducing platelet destruction and increasing platelet
production. Diagnosis requires exclusion of other causes of
thrombocytopenia, including infectious, malignant, and drug-
induced causes (Cines et al., 2009).
Therapy depends on the overall clinical situation, including
platelet counts, patient history, and bleeding symptoms.
Therapy is usually considered for platelet counts below
20 000 ml 1 or for any clinically signicant bleeding. The most
rapid clinical response is usually seen with either intravenous
immunoglobulins or anti-RhD immunoglobulin, both block
the macrophages within the spleen and liver from clearing the
autoantibody-coated platelets. High-dose steroids may be
given at the same time to maximize response. TPO receptor
agonists can increase platelet counts in ITP patients not
otherwise responsive to standard therapy. In a life-threatening
situation, an emergency splenectomy may rapidly raise the
platelet count.
Drug-Induced Immune Thrombocytopenia
Occasionally a drug can bind to either platelets or plasma
proteins and act as a hapten, creating a new protein confor-
mation that is recognized by the body as foreign antigen. This
new antigen then elicits an immune response, resulting in an
autoantibody against the drug and its binding partner. Platelets
are then destroyed either by immune complex or compliment-
mediated lysis. Many drugs have been implicated in immune-
mediated thrombocytopenia. Penicillins and dilantin are
frequent causes. Thrombocytopenia can be severe, with
mucocutaneous bleeding, but it usually recovers within 2 days
after stopping the drug. Some drugs implicated in this process
are listed in Table 2.
Heparin-induced thrombocytopenia is a special case of
drug-induced ITP. The mechanism is heparin combining with
platelet factor 4 (PF4) to form a neoantigen complex. PF4 is
stored in platelet a-granules and released upon activation. The
autoantibody and heparin/PF4 complexes combine to form
immune complexes, which cause platelet activation and
thrombocytopenia. The immune complexes also result in
generation of procoagulant platelet-driven microparticles,
leading to thrombin generation. The vascular wall is also
damaged by the immune complexes, leading to the release of
tissue factor and further thrombin generation. The end result is
a highly thrombotic state characterized by arterial as well as
venous thrombosis. Treatment is with an anticoagulant that
does not contain heparin, such as a direct thrombin inhibitor.
Platelets and Pathology
As the body ages, the inside of the blood vessels can become
damaged and buildup of platelets and circulating lipids can
 Platelets 5

Table 2 Drugs commonly implicated in immune-mediated anti-aIIbb3 agents are the cyclic peptide eptibatide and the
thrombocytopenia small molecule tiroban. Drugs targeting the P2Y(12) receptors
are another widely used class of antiplatelet agents. These
Anti-microbials
include clopidogrel, prasugrel, and ticagrelor. The P2Y(12)
lLinezolid
lAmphotericin receptors mediate the second wave of platelet activation
lTetracyclines through binding of ADP. These agents prevent secondary acti-
lSulfonamides vation of platelets and thus prevent propagation of clotting
lPenicillins past the initial platelet monolayer.
lChloramphenicol
lCephalosporins
Anti-convulsants Platelet Functions beyond Hemostasis
lPhenytoin (dilantin)
lCarbamazepine Although the primary role of platelets is to prevent bleeding,
they also play diverse roles in other important physiological
Diuretics
lFurosemide processes. Platelets release proinammatory, antiinammatory,
lThiazides and angiogenic factors into the circulation. Platelets recruit
lEthacrynic acid leukocytes to areas of vascular injury. Platelets also release tiny
membrane particles, called microparticles that can amplify the
Others
thrombotic and other functions of platelets in circulation.
lAlcohol
lPhenylbutazone Remarkably, despite not having a nucleus, platelets can produce
lAspirin some of these proteins de novo upon activation by splicing pre-
lGold salts mRNA into mRNA and translating this into new proteins.
lColchicine These are important normal platelet functions, but they can also
lChlorpromazine contribute to atherosclerosis, heart attack, stroke, acute lung
lChlordiazepoxide injury and transplant rejection. Some of these functions are
lH2 blockers described below.
Platelets contain numerous bioactive molecules that they
store and release upon activation (Table 1). Several proin-
occur, leading to the formation of atherosclerotic plaques. ammatory cytokines are secreted, including IL-1b, which is an
Rupture of these plaques activates platelets and inappropriately important initiator of inammation. Conversely, platelets also
initiates blood clotting. If this occurs in the heart or brain, heart secrete TGF-1b, which is an important suppressor of inam-
attack or stroke may result. Thus a part of the therapy for these mation. In this way platelets actively participate in immune
diseases is directed at blocking the platelet function to prevent modulation at sites of platelet activation. However, this process
further inappropriate clotting. can also contribute to pathology, such as in rheumatoid
arthritis, in which platelets play a role in the immune dysre-
gulation. Platelets also secrete potent angiogenic factors, such
Platelet Inhibitors
as vascular endothelial growth factor. These factors help to
The most commonly used antiplatelet drug is aspirin, which induce growth of new blood vessels at sites of injury. This
permanently disables the enzyme cyclooxygenase, thereby function is important for normal wound healing but may also
preventing the platelet from producing thromboxane-A2. be subverted by cancer cells to provide blood supply for tumor
Without thromboxane-A2, the platelet is inhibited from growth (Smyth et al., 2009).
responding to many thrombotic stimuli. Dipyridamole is Platelet interaction with leukocytes also has important
another widely used antiplatelet drug. While its mechanism is functions in immune regulation. Platelets expose P-selectin on
not completely understood, it is thought to interfere with their surface when they are activated. This molecule binds to
ADP-mediated platelet activation by inhibiting phosphodies- leukocytes and can recruit leukocytes to sites of vascular injury.
terases. Omega-3 fatty acids also have an antiplatelet effect. The Platelets can then activate those leukocytes, causing a local
omega-3 fatty acids decrease platelet responsiveness to stimuli inammatory reaction. This is part of the normal immune
by incorporating into and changing the uidity of the platelet process, but can be pathological as in the case of sickle cell
membrane (Michelson, 2010). vascular inammation, transfusion related acute lung injury,
Blocking or inhibiting platelet surface receptors can interfere and transplant rejection. Platelets also play a direct role in
with platelet activity. There are two major classes of antiplatelet innate immunity by binding to certain pathogens in the blood
drugs, both of which have been highly effective in preventing and directly removing them from circulation. All of these
atherosclerosis-related deaths. The rst receptor is the aIIbb3 platelet functions intimately link the hemostatic and immune
receptor, which is the most densely populated receptor in the functions of the body.
body, with 80 000 copies per platelet. This receptor is the
primary initiator of platelet aggregation, and these agents
induce profound platelet dysfunction. Abciximab was the rst Conclusion
of these drugs and was the rst humanized monoclonal
antibody brought to market. It is a chimera of a mouse anti- Although once thought to participate only in the process of
aIIbb3 antibody and a human Fc antibody chain. Other clot formation, platelets are now recognized to play roles in
6 Platelets
many important pathological processes. These tiny anucleate
cells participate in immunity and inammation, are patho-
genic in heart attack and stroke, and play important roles in
angiogenesis. They can also be coopted to maintain tumor
blood supply and help tumors metastasize. Current research
continues to explore these and other platelet functions, such
as their roles in would healing, transplant rejection, and sickle
cell disease vasculopathy. As our understanding of platelet
physiology in these progresses grows, new opportunities for
therapies involving these diverse processes will continue to
emerge.
See also: Atherosclerosis; Blood Products; Microangiopathic
Hemolytic Anemia; Pathophysiology of Sickle Cell Disease;
Perinatal Alloantibody Disorders Neonatal Alloimmune
Thrombocytopenia/Hemolytic Disease of the Fetus and
Newborn; Platelet Disorders (Inherited and Acquired); The
Molecular Basis of Blood Coagulation; von Willebrand Disease.
References
Brass, L., 2010. Understanding and evaluating platelet function. Hematol. Am. Soc.
Hematol. Educ. Program 2010, 387396.
Cines, D.B., Bussel, J.B., Liebman, H.A., Luning Prak, E.T., 2009. The ITP syndrome:
pathogenic and clinical diversity. Blood 113 (26), 65116521.
George, J.N., 2000. Platelets. Lancet 355 (9214), 15311539.
Hartwig, J., Italiano Jr., J., 2003. The birth of the platelet. J. Thromb. Haemost. 1 (7),
15801586.
Josefsson, E.C., White, M.J., Dowling, M.R., Kile, B.T., 2012. Platelet life span and
apoptosis. Methods Mol. Biol. 788, 5971.
Michelson, A.D., 2010. Antiplatelet therapies for the treatment of cardiovascular
disease. Nat. Rev. Drug Discov. 9 (2), 154169.
Smyth, S.S., McEver, R.P., Weyrich, A.S., et al., 2009. Platelet functions beyond
hemostasis. J. Thromb. Haemost. 7 (11), 17591766.
Relevant Websites
http://www.aabb.org/.
http://www.redcrossblood.org/learn-about-blood/blood-components/platelets.