TATM

Transfusion Alternatives in Transfusion Medicine

Platelet biology an overview

THOMAS S. KICKLER, M D

Department of Pathology, Johns

Hopkins University, School of
Medicine, Baltimore, MD, USA
Correspondence to:
T. Kickler, Professor of Medicine and
Pathology, Department of Pathology,
Johns Hopkins Hospital, 401 N.
Broadway Street, Room 2333,
Baltimore, MD 21231, USA
E-mail: tkickler@jhmi.edu

Publication data
Submitted: 29 April 2005
Accepted: 3 May 2005

SUMMARY

Understanding the biology of platelet is important for one to treat

patients with acquired or inherited platelet disorders. Platelets provide
primary hemostasis by performing five primary functions: adhesion,
aggregation, secretion, and providing procoagulant surface and clot
retraction. The elucidation of the molecular mechanisms carrying out
these functions has led to a better understanding of the pathophysiology
of bleeding and the development of new approaches in treating patients
with qualitative and quantitative platelet disorders. The purpose of this
review is to provide a foundation for understanding the other papers in
this publication on the treatment of platelet disorders.

Keywords
Acquired bleeding disorders
Hemostasis
Platelets

HEMOSTASIS
Hemostasis is the complex physiologic process that
leads to the arrest of bleeding. It consists of three
components: (i) platelets; (ii) plasma proteins; (iii) blood
vessels and endothelial cells.1
With injury to a vessel, the forces of all three components are quickly brought to bear. Blood vessels constrict, platelets aggregate to form a plug, the plug is
stabilized by the formation of insoluble fibrin due to
the action of thrombin on soluble fibrinogen.
Blood fluidity is maintained by checks and balances: blood coagulation is normally held in check
by a series of enzymes comprising the fibrinolytic
pathway, which restores vascular patency. A complex
series of anticoagulants also inhibit the formation of
intravascular thrombin. Disruption of these balances

leads to clinical bleeding or thrombus formation

(Figure 1).2

Platelets
Platelets are produced in the bone marrow megakaryocytes stimulated by the growth factor thrombopoietin.
The normal platelet concentration is 150,000350,000/
L. Platelets circulate in the blood for 10 days.3

OVERVIEW OF PLATELET FUNCTIONS

Adhesion
The adhesion molecule von Willebrand Factor (vWF)
binds to subendothelium which then allows platelets to

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Journal Compilation 2006 LMS Group Transfusion Alternatives in Transfusion Medicine
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80 KICKLER | PLATELET BIOLOGY

adhesive molecules, fibrinogen, vWF, thrombospondin

and fibronectin, which promote additional adhesion and
aggregation. ADP promotes more platelet activation and
thromboxane A2 promotes blood vessel constriction.
With secretion shape changes leading to pseudopodia
occur which facilitate aggregation to other platelets.6

Vessel injury
vWF

Tissue factor
VIIa

IXa
Xa

Subendothelial
collagen

VIIIa

Va
Thrombin

Platelet
adhesion
Epi
ADP
TXA2

Fibrinogen
Fibrin

Platelet
aggregates

Hemostatic plug

Figure 1. Overview of hemostasis. a activated form of

clotting factor V, VII, VIII, IX, X; ADP, adenosine
diphosphate; Epi, epinephrine; TXA2, thromboxane; vWF,
von Willebrand factor.

adhere to the injury site, and occurs within 13 seconds

after an injury.4

Secretion
Intracellular signaling (platelet activation)
A variety of platelet agonists, including thrombin generated from the clotting cascade, epinephrine, collagen
from the subendothelium, and ADP, cause intracellular
signaling leading to secretion.
Platelets have at least five functionally different guanine nucleotide-binding proteins, or G proteins. Once an
agonist-like thrombin binds to its receptor, its associated
G protein releases GDP, binds GTP and activates a
signal-generating enzyme, such as phospholipase C.
Phospholipase C hydrolyzes the precursor inositol phospholipid PIP2 into the second messengers inositol 1,4,5triphosphate (IP3) and 1,2-diacylgylcerol (DAG). IP3
causes an increase in intracellular calcium and DAG
activates protein kinase C (PKC) and these molecules
effect secretion, shape change and aggregation.5

The secrete life of a platelet

Upon activation, platelets secrete the contents of the
dense granules (DG) which contain calcium, ADP, ATP,
GTP, thromboxane and serotonin. Alpha granules (AG)
fuse to the plasma membrane and release their contents
upon platelet activation. These granules contain the

Aggregation
Platelets bind to each other. Formation of this platelet
web is the result of the binding of fibrinogen to glycoprotein IIbIIIa, an integrin molecule that only binds
fibrinogen after the molecule undergoes a conformational change, the result of the above described platelet
activation processes.
The amino acid sequences of GPIIb and GPIIIa helped
define a family of adhesion molecules that have come to
be known as integrins. Integrins are a family of structurally related glycoproteins that consist of alpha and
beta subunits, and bind adhesive molecules (like fibrinogen). The term integrin was coined to refer to an integral membrane protein that served as a bridge between
the extracellular matrix and the cytoskeleton of the cell.
GPIIbIIIa belongs to a subclass of integrins characterized by their ability to bind ligands containing
the amino acid sequence: arginine-glycine-aspartic
acid-serine (RGDS). Fibrinogen is rich in RGDS
sequences.7

Platelet procoagulant activity

The activated platelet membrane permits the binding of
clotting proteins Factor V and X complex, leading to
greatly increased catalytic activity of these plasma factors. It does this by providing phospholipid binding sites.8
The above takes 34 minutes, and can be measured
in a patient by doing a bleeding time (a simple test done
by making a small incision on the forearm, and measuring how long it takes to form a clot).
These processes can be summarized as in (Figure 2).
RECEPTORS INVOLVED IN ADHESION,
SECRETION AND AGGREGATION

Platelet adhesion (Figure 3)

The major vWF receptor on platelets is the glycoprotein
IB-IX complex. This complex is comprised of four sub-

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KICKLER | PLATELET BIOLOGY

81

Adhesion

vWF
binds to
subendothelium
Platelets

Weibel-Palade
Body

Secretion

Figure 3. Overview of platelet adhesion involving platelet

glycoprotein receptor (GPIb-IX) and vWF (von
Willebrand factor).

ADP
TxA2

Platelet
activation

Aggregation and activation of clotting

Clotting cascade
activation
Fibrin
Phospholipid

Figure 4. Overview of the effect of thrombin upon

platelets and the process of secretion.

Aggregation (Plateletplatelet adhesion)

Figure 2. Overview of the three main platelet functions of

adhesion, secretion and aggregation. ADP, adenosine
diphosphate; TXA2, thromboxane; vWF, von Willebrand
factor.

units: GPIb, GPIb, GPIX and GPV. Its importance is

underscored by the severe bleeding that occurs with its
congenital absence. Acquired antibodies to the protein
may block its function.9

Platelet secretion (Figure 4)

The most potent of these includes thrombin, which
belongs to a family of molecules that span the plasma

membrane seven times with a long amino terminus

exterior to the cell and a short intracellular terminus.
Thrombin activates its receptor in a unique function by
cleaving a portion of the distal end of the receptor
generating a new amino terminus which in turn interacts with another region of the receptor to generate is
activation signal. To date no deficiency in the thrombin
receptor has been identified.10

Platelet aggregation (Figure 5)

Platelet adhesion to other platelets is referred to as
platelet aggregation and is to be distinguished from
platelets interacting with the subendothelium. Aggregation requires the binding of fibrinogen to its receptor
on activated platelets. In the resting state, fibrinogen

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82 KICKLER | PLATELET BIOLOGY

Figure 5. Overview of platelets aggregation to other

platelets by fibrinogen binding to platelet glycoprotein
IIbIIIa.

does not bind to platelets, but with activation conformational changes of the fibrinogen receptor occur permitting fibrinogen binding.
The fibrinogen receptor on platelets is a calciumdependent complex of two non-identical glycoproteins,
GPIIb and GPIIIa. There are 80,000 copies of this receptor on platelets making it the most abundant receptor.11
The amino acid sequence of GPIIb and IIIa helped
define a family of adhesion molecules that have been
named the integrins. Integrins are a family of structurally related glycoproteins that consist of and subunits and bind adhesive proteins. The term integrin was
coined to refer to integral membrane proteins that serve
as a bridge between extracellular matrix and the cytoskeleton of the cell.
Absence of GPIIbIIIa leads to thrombasthenia, a condition characterized by severe bleeding.
This integrin is polymorphic and is an important
immunogen in causing immune mediated thrombocytopenia (see below).
PATHOPHYSIOLOGY OF QUALITATIVE
PLATELET DISORDERS
Quantitative platelet disorders are molecular lesions of
the above described molecules leading to platelet dysfunction, inherited or acquired (Figure 6).12

Inherited disorders of platelet function

Aggregation
The most common inherited disease of platelets is
Glanzmann thrombasthenia. This is an autosomal

Figure 6. Overview of normal platelet function. PLC, PIP2,

PLA2, MLC, PGH2 represent steps in thromboxane
synthesis. ADP, adenosine diphosphate; PLT, platelet; RG,
receptor and G linked proteins; TBX-A, thromboxane.

recessive disorder characterized by mucocutaneous

bleeding of mild-to-moderate severity from the time
of birth. The platelet count is normal, the platelets
appear normal, the bleeding time is prolonged and
platelet aggregation to all physiologic stimuli is
absent. The vast majority of cases are due to virtual
absence of the GPIIbIIIa fibrinogen receptor. Because
both subunits are required for assembly and surface
expression, the absence of one glycoprotein results in
the eventual intracellular degradation of the unpaired
partner.13

Adhesion
Inherited defects leading to absence of the GPIb protein are seen in classical BernardSoulier syndrome.
These patients bleed because of an inability to bind vWF
and hence, adhere to subendothelium. Often they have
a slightly low platelet count and large platelets on the
peripheral blood smear.14

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KICKLER | PLATELET BIOLOGY

Secretion
The storage pool diseases are characterized by a lack
of DG, AG, or a specific component of one of the
granules (classically, ADP). Bleeding is mild-to-severe
and in vitro platelet aggregation studies are
diminished.15

83

activation, platelets demonstrate a remarkable change

in morphology, changing from the discoid shape to a
smaller, contracted sphere with long filamentous
pseudopodia. This provides up to 50% additional surface
area for contact with other platelets and subsequent clot
retraction (Figure 8).

Acquired disorders of platelet function

Drugs, toxins built up during renal failure, physical
trauma when the blood is exposed to extracorporeal
circulation in heart surgery, dietary agents (omega 3
fatty acid from fish oil) may all interfere with platelet
function.16
Aspirin is a common non-prescription drug affecting
platelet function. The basis of this is as follows
(Figure 7):

PLATELET HISTOLOGY
Platelets are not true cells, but fragments of megakaryocytes. The drawing below shows the canalicular system
(CS) that permits the ingress and egress of molecules
needed for hemostasis and transport. The DG contain
serotonin, ADP, ATP and thromboxane. The AG release
fibrinogen, and vWF. There are abundant mitochondria
(M).17
An extensive system of microtubules (MT) maintains
the normal, resting discoid shape of the platelet. Upon

Figure 8. Platelet histology. G, alpha granules; CS,

canalicular system; DG, dense granules; M, mitochondria;
MT, microtubules; PM, plasma membrane; SMF, simple
membrane filament.

PLATELETENDOTHELIAL INTERACTIONS
(Figure 9)

ASA

Phospholipase

Arachidamic Acid
Cyclooxygenase
PGG2/PGH2

Thromboxane A2
activates platelet

Thromboxane B2

Dehydrogenase

TXA Synthase

11-dehydro
Thromboxane B2

Figure 7. Overview of thromboxane production.

Under normal conditions platelets do not adhere to

endothelial cells. The non-thrombogenic nature of
endothelial cells is due to both passive factors (a negative charge on its surface) and numerous active processes. Prostacyclin (also called PGI2) is a vasodilator
and inhibits platelet activation by raising cyclic AMP
levels. Endothelial cells also release endothelial-derived
releasing factor (EDRF) or nitric oxide (NO) which can
inhibit platelet function.18
In addition, tissue plasminogen activator (tPA) promotes lysis of clots. Thrombomodulin (TM) serves to
inactivate clotting proteins by inhibiting thrombin. An
ADPase catalyzes the destruction of ADP, decreasing
platelet activation.

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84 KICKLER | PLATELET BIOLOGY

Figure 9. Overview of the effect of the endothelium upon

platelet function. AMP, adenosine monophosphate;
cAMP, cylic adenosine monophosphate; EDRF,
endothelial releasing factor; eNOS, endothelial nitric
oxide synthetase; GTP, guanine triphosphate; HEP,
heparin; NO, nitric oxide; PGI2, prostocyclin; TM,
thrombomodulin; tPA, tissue plasminogen activator.

Figure 10. Overview of thrombopoiesis.

THROMBOCYTOPENIA

Thrombopoiesis
Thrombopoietin is a potent megakaryocyte-stimulating
factor, acting in synergy with a variety of cytokines.
Although these cytokines support several aspects of
megakaryocyte development in vitro, genetic elimination

(knockout animals) only steel factor (stem cell factor)

and thrombopoietin affects megakaryocyte and platelet
production in vivo. Thrombopoietin also primes platelets
to be more sensitive to platelet agonists. A recombinant
form of thrombopoietin is available to increase platelet
production in thrombocytopenic patients, although its
clinical indications are relatively limited (Figure 10).19

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REFERENCES
1 Roberts HR, Lozier JH. New perspectives
on coagulation cascade. Hosp Prac 1995;
27: 97112.
2 Schaefer AI. Coagulation cascade: an
overview. In: Lascalzo J, Schaefer AI (eds).
Thrombosis and Hemostasis. Blackwell:
Boston, MA, 1994, pp. 312.
3 Kaushansky K. Thrombopoietin. The primary regulator of platelet production.
Blood 1995; 86: 41931.
4 Nurden AT, Caen JP. Specific roles for
platelet surface glycoproteins in platelet
function. Nature 1975; 255: 7202.
5 Neer EJ. Heterotrimeric G proteins: organizers of transmembrane signals. Cell
1995; 80: 24957.
6 White JG. Use of the electron microscope
for diagnosis of platelet disorders. Semin
Thromb Haemost 1998; 24: 1638.
7 Ginsberg MH, Loftus JC, Plow EF. Cytoadhesions, integrins and platelets. Thromb
Haemost 1988; 59: 16.

8 Rosing J, Tans G, Govers-Riemslag JW,

Zwaal RF, Hemker HC. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1990; 255:
27483.
9 Lopez JA. The platelet glycoprotein IB-IX
complex. Blood Coagul Fibrinolysis 1994;
5: 97103.
10 Jamieson GA. Pathophysiology of platelet
thrombin receptors. Thromb Haemost
1997; 78: 2426.
11 Shattil SJ, Gao J, Kashiwagi H. Not just
another pretty face: regulation of platelet
function at the cytoplasmic face of integrin IIB B3. Thromb Haemost 1997; 78:
2205.
12 Rao AK, Holmsen H. Congenital disorders
of platelet function. Semin Hematol 1986;
23: 10218.
13 Nurden AT, Caen JP. An abnormal glycoprotein pattern in three cases of
Glanzmanns thrombosphenia. Br J
Haematol 1974; 28: 25360.
14 Bernard J, Soulier J. Sur une nouvelle

2006 The Author

Journal Compilation 2006 LMS Group Transfusion Alternatives in Transfusion Medicine 2, 7985

15

16

17

18

19

85

varit de dystrophie thrombocytaire

hmorragipare congnitale. Semin Hop
Paris 1948; 24: 321723.
Rao AK. Congenital disorders of platelet
secretion and signal transduction. In:
Coleman RW, Hirsh J, Marder VJ, Clowes
P, George JN (eds). Hemostasis and
Thrombosis: Basic Principles and Clinical
Practice, 4th edn. JB Lippincott: Philadelphia, PA, 2001, pp. 890904.
George J, Shattel SJ. The clinical importance of acquired abnormalities of platelet
function. N Engl J Med 1991; 324: 2739.
White JG. An overview of platelet structural physiology. Scan Microsc 1988;
1677700.
Willoughley S, Loscalzo J. Vascular control of platelet function. In: Gressle P,
Page CP, Fuster V, Vermylen J (eds). Platelets. Cambridge Press: Cambridge, UK,
2002, pp. 43253.
Kaushansky K. Thrombopoietin from theory to reality. Thromb Haemost 1999; 82:
31217.