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Haemophilia (2008), 14, 1240–1249 DOI: 10.1111/j.1365-2516.2008.01898.

ORIGINAL ARTICLE

Platelet function defects


D. SIMON,* T. KUNICKI  and D. NUGENT*
*From the ChildrenÕs Hospital of Orange County, Orange; and  The Scripps Research Institute, La Jolla, CA, USA

Summary. Inherited defects of platelet function are aIIbb3 receptor is the prototypical defect of the
a heterogeneous group of disorders that can result cohesion/aggregation phase of microthrombi for-
in bleeding symptoms ranging from mild bruising mation. Many of these disorders share common
to severe mucocutaneous haemorrhage. These treatments although some therapies will have
defects may be classified according to their effect greater efficacy for one patient than another and
on the various steps of platelet microthrombi should be individualized so as to provide optimal
formation including initiation, extension and cohe- control of symptoms. Currently much effort is
sion, or based on their particular structural or being put into methods to more rapidly and
functional deficiency. Platelet membrane receptor accurately diagnose patients with platelet disorders
deficiencies result in the rare, but well-character- and to initiate appropriate therapy and prevent life
ized syndromes of defective clot initiation, such as threatening bleeding.
Bernard–Soulier Syndrome. Platelet storage pool
defects are the most common disorders affecting Keywords: bleeding disorders, clot formation, plate-
the extension phase of clot formation. Glanzmann let function, platelet granules, platelet membrane
thrombasthenia, with absent or dysfunctional receptors, platelets

thrombocytopenia, which are not covered here,


Introduction: normal platelet function
have been published in the last few years and are
The formation of a stable platelet plug hinges on highly recommended to the reader [1,2].
the ability of the platelet to interact with the
damaged vascular bed and recruitment of other
Adhesion
cells in the process of haemostasis and repair. Any
defect in this process can cause bleeding symptoms, The first step in the initiation phase of thrombus
ranging from clinically insignificant to severe. formation involves plasma von Willebrand factor
Platelet defects can be classified by their location (VWF) binding to exposed collagen on the
in the three phases of clot formation: initiation, subendothelium via its VWF-A1 domain while
extension, and cohesion or aggregation or based on simultaneously binding to the platelet membrane
their particular structural or functional deficiency glycoprotein (GP) Ib-IX-V complex (Fig. 1a).
(Schema 1). Although it would be impractical to Platelets also bind directly to collagen via the
summarize all known platelet qualitative defects, membrane GPVI receptor complex and the integrin
some of the well-characterized and clinically sig- a2b1 collagen receptor [3,4]. This process results in a
nificant syndromes will be discussed here with a stable layer of platelets to facilitate the formation of
focus on presentation, diagnosis and treatment. the platelet plug. Bernard–Soulier syndrome (BSS) is
Additional excellent and more detailed articles on characterized by the absence of the platelet mem-
inherited platelet disorders, including congenital brane GPIb complex and thus is the prototypical
mutation that affects initiation because this defect
Correspondence: Diane Nugent, MD, ChildrenÕs Hospital of prevents normal adhesion to the VWF-A1 domain
Orange County, 455 S Main St, Orange, CA 92868, USA. [5]. The normal engagement of these receptors and
Tel.: +714 532 8744; fax: +714 532 8771; the formation of the platelet monolayer enhances
e-mail: djn0@choc.org platelet activation and signals the onset of the next
Accepted after revision 18 August 2008 stage of microthrombus formation.

Ó 2008 The Authors


1240 Journal compilation Ó 2008 Blackwell Publishing Ltd
PLATELET DEFECTS 1241

(a) Adhesion (b) Extension

Initiation of secretion
Blood flow direction and membrane
activation

GP Ib-IX-V
Ib IX V

VWF VWF GP VI
Collagen Collagen

Most Common Inherited Platelet Defects


(c) Cohesion/Aggregation Glanzmann
Thrombasthenia Bernard-Soulier Syndrome
Secretion, thrombin and prothrombinase activity extends microthrombi formation
Ibβ Ibα
IX
IIbIIIa V
Fibrin
monomer Altered response to Altered
VI collagen
agonists: ADP, TXA2,
Epinephrine, etc. binding

α2β1

Scott Syndrome

αIIbβ3
α-granule Defects Dense Granule Defects
Fibrinogen -Gray Platelet Syndrome -Hermansky-Pudlak Syndrome
-Chediak-Higashi Syndrome
-Quebec Platelet Syndrome
-α-SPD Cytoskeletal Defects -Griscelli Syndrome
VWF
αIIbβ3
-α,δ-SPD -δ-SPD
-Wiskott-Aldrich Syndrome
-MYH9 and associated
giant platelet disorders

Fig. 1. Figs 1a, b and c outline the three phases of platelet plug formation including adhesion (1a), extension (1b) and aggregation/cohesion
with clot formation. Each step requires a coordinated response to ligand and receptor interactions, signaling molecules, membrane
expression of clotting protein components, secretion of granule contents, and cytoskeletal modifications. Abnormalities in any of these
components will result in platelet dysfunction, although some maybe much more serious than others, based on the presence or absence of
alternative pathways to complete the clot formation.

far, storage pool defects appear to be the most


Extension
common of these disorders, but membrane receptor
During this phase, adherent platelets become acti- and signal transduction pathway abnormalities are
vated and secrete stored compounds from their an active area of ongoing research.
a-granules and d-granules (Fig. 1b). This stimulates Another defect related to the extension phase of clot
circulating platelets to activate and release, which formation is the rare autosomal recessive disorder
greatly enhances the propagation of the platelet plug. Scott Syndrome [8]. Patients affected by Scott Syn-
A key compound includes adenosine diphosphate drome ultimately have impaired platelet dependant
(ADP), which helps to further activate platelets fibrin formation leading to a potentially significant
through binding to the respective ADP receptors on bleeding disorder. Scott syndrome is fundamentally a
neighbouring platelets. During the course of this signal transduction pathway defect. Upon activation,
process, the activated platelet produces and/or Scott platelets are unable to transport phosphatidyl-
releases additional agonists, including thromboxane serine from the inner to the outer phospholipid
A2 (TXA2). This is also the likely stage at which the membrane. Consequently, the factor Va–Xa and
activated platelet surface prothrombinase catalyzes VIIIa–IXa complexes are unable to bind to the
the conversion of prothrombin providing a platform membrane resulting in decreased thrombin generation
for fibrin clot propagation [6]. Numerous platelet and subsequently inadequate fibrin formation. Muta-
defects that involve the extension phase of clot tions of an ATP-binding cassette transporter A1
formation have been previously described [7]. Thus (ABCA1) are partly responsible for phosphatidylser-

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Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 1240–1249
1242 D. SIMON et al.

ine translocation and have been implicated in the and may aid in the diagnostic work-up and choice of
pathogenesis of Scott Syndrome [8,9]. therapy.

Cohesion/aggregation General diagnostic evaluation


The final step in forming a platelet-rich thrombus is For the majority of haematologists, the diagnosis of
the cohesion/aggregation phase (Fig. 1c). Plasma platelet dysfunction is limited to a general category
VWF and fibrinogen bind activated platelets together based on the combination of aggregation studies,
via the platelet integrin aIIbb3 (GPIIb–IIIa) complex. evaluation of the platelet on smear, and in some
The classic disease state that results in a defective centres, flow cytometry and electron microscopy.
consolidation phase of clot formation is Glanzmann Reference centres can provide more specialized
thrombasthenia (GT), which results in decreased studies in the measurement of ATP/ADP levels,
levels or function of the GPIIb–IIIa complex, leading characterization of granules or signalling defects.
to absent or severely reduced platelet aggregation This remained the state of the art until the most
[10]. recent decade, which brought the promise of more
Thrombocytopenia whether inherited or acquired exact diagnosis based on specific molecular and
will impact all three phases to varying degrees based proteomic screening techniques, thus allowing hae-
on the severity of the platelet deficiency. In a healthy matologist to provide counselling for patients and
individual, the platelet count must fall below families based on their own unique mutations.
20 000–30 000 mm)3 before significant mucocuta- Platelet Function Evaluation: In decades past,
neous bleeding will occur. In high turnover states, initial studies used the bleeding time as the main-
such as immune mediated thrombocytopenic pur- stay of diagnostic manoeuvres to identify patients
pura, the platelets are younger overall, slightly larger with platelet dysfunction [12]. Milder forms of
and more haemostatic, and so the platelet count may platelet disorders could be elicited by administration
fall to <15 000 mm)3 before serious bleeding occurs. of aspirin, which resulted in prolongation of the
Other defects that warrant special consideration in bleeding time, in these patients but not in indi-
the hereditary thrombocytopenias are the MYH-9 viduals with normal platelet function. Although
family of giant platelet disorders and Wiskott– still very useful in diagnosis of platelet dysfunction,
Aldrich Syndrome with minute Ôdust-likeÕ platelets, the bleeding time has fallen out of favour because
both of which are associated with bleeding and of its unreliability for presurgical screening, partic-
striking morphology on the peripheral smear. These ularly in patients with renal disease or with skin
syndromes can be diagnosed with a simple CBC; for changes associated with medications or collagen
that reason, the importance of reviewing the smear in defects. As a result, it is no longer widely available
any evaluation of platelet disorders cannot be over and very few clinical laboratories have technicians
stressed. Inherited thrombocytopenic syndromes are who can perform this assay well, especially on
covered elsewhere in a recent review by Nurden et al. children.
[11]. Once von Willebrand disease, the most common
diagnosis associated with mucosal bleeding has been
excluded, the patients referred for evaluation of
Incidence, racial/ethnic predilection
platelet dysfunction may have a number of studies
Fortunately, the severe forms of congenital platelet performed either in series or with the initial visit.
dysfunction are extremely rare. While it has been Importantly, no single assay or technology can
suggested that some of the disorders may be under diagnose all platelet disorders. Many facilities use
diagnosed, some are known only to occur in a the platelet function analyzer (PFA-100) or platelet
handful of families worldwide. Therefore, these thromboelastography in whole blood as an initial
defects are much more common in areas where screen for platelet dysfunction prior to surgical
consanguinity is more prevalent or in small, geo- procedures [13]. Further evaluation is necessary to
graphically or ethnically isolated communities. In the actually define the platelet defect and may include;
more common secretory defects, compound hetero- platelet aggregation with various agonists [14],
zygote mutations are more frequent. Rarely, the calcium flux or secretion studies, protein biochemis-
family history may suggest an autosomal dominant try, electron microscopy and flow cytometry. Unlike
pattern with mucocutaneous bleeding present in congenital thrombocytopenia syndromes, such as
multiple generations. As with all rare blood diseases, MYH9 defects or Wiscott Aldrich, there is not yet
the age of onset and family history is very important a molecular screen that could bypass the initial

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PLATELET DEFECTS 1243

Table 1. Summary of platelet defects.


Diagnosis Phase of clot formation Key diagnostic findings Thrombocytopenia?
Bernard–Soulier syndrome Initiation Lack of GPIb-IX-V Mild
Impaired aggregation to ristocetin
Giant platelets
a-SPD (gray platelet syndrome) Extension Lack of a-granules on EM Mild to moderate
Large, gray, agranular platelets
d-SPD Extension Lack of d-granules on EM None
Reduced secondary wave of aggregation
Low levels of platelet ADP, ATP
Chediak–Higashi syndrome Extension Oculocutaneous albinism None
d-granule defects
Progressive neurological deterioration
Cytoplasmic inclusions
Hermansky–Pudlak syndrome Extension Oculocutaneous albinism None
d-granule defects
Pulmonary fibrosis
ad-SPD Extension Defects in primary and secondary aggregation None to mild
Lack of a- and d-granules on EM
Glanzmann thrombasthenia Consolidation/aggregation Lack of GPIIb–IIIa None
Poor aggregation with ADP, collagen, Epi
Normal ristocetin induced aggregation
Absent clot retraction
Morphologically normal platelets
ADP, adenosine diphosphate; ATP, adenosine triphosphate; EM, electron microscopy; GP, glycoprotein; SPD, storage pool disease.

functional or biochemical evaluation in platelet In any event, the patients should have a reliable
dysfunction. way of contacting their haematologist, or providing
Not all these assays are required for each diagno- their surgeons or ER physicians with a treatment
sis, however. Ongoing studies and working groups plan in the event prophylaxis is needed or bleeding
are validating, which are most useful for each occurs. All patients with platelet defects must be
diagnosis, to streamline the diagnostic workup, counselled on avoiding certain medications that
particularly in children [14,15]. A table summarizing interfere with platelet function, such as aspirin and
pertinent findings for the syndromes described in this many non-steroidal anti-inflammatory agents or
clinical review is listed in Table 1. In the future, certain antidepressants [16].
platelet proteomics or molecular arrays may speed Women with menorrhagia may require hormonal
up the process of diagnosis by identifying upfront suppression to prevent menses altogether while
which protein or DNA sequence is defective or others have undergone uterine ablation or hysterec-
absent, but functional assays are still required today tomy to prevent life threatening bleeding in the most
and will be for some time. extreme cases. A comprehensive team approach is
necessary for these patients and should include a
gynaecologist with a special interest in bleeding
General approach to treatment
disorders [17,18].
Because the treatment is similar for these syndromes, In general, certain non-specific agents have been
a brief review of the common therapeutic regimens used for years to minimize mucosal bleeding or as
used in platelet dysfunction will be discussed here prophylaxis for minor surgical bleeding. Antifibrino-
and additional treatments unique to one particular lytic agents such as -aminocaproic acid (Amicar) or
disorder will be included under that specific heading. tranexamic acid (Cyklokapron) have been used with
The first step in treatment and prevention of bleeding some success to decrease mucosal bleeding associated
is always education of the patient and the family. All with epistaxis, menses or mucosal bleeding after
must be counselled that mucocutaneous bleeding will dental work. In addition, desmopressin acetate
be common. Serious haemorrhage can occur in the (DDAVP) has been shown to be effective in prevent-
event of trauma, surgery, in the gastrointestinal tract ing the bleeding in some of the platelet dysfunction
and frequently with menses or the postpartum syndromes [19]. A trial of DDAVP should always be
period. performed to determine response before its use to

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1244 D. SIMON et al.

prevent bleeding prophylactically, as DDAVP has trimers then associate non-covalently with one mol-
been known to trigger fibrinolysis in certain patients. ecule of GPV to form the GPIb-IX-V complex. BSS is
Many articles have been published recently using characterized by the inability of platelets to bind to
activated recombinant factor VII (rFVIIa) to slow or VWF during the initial steps of platelet adhesion
arrest bleeding associated with platelet dysfunction because these platelets either lack or have a qualita-
[20,21]. Dosages have varied widely, but many tive defect in the platelet membrane glycoprotein
patients have responded to this regimen when others GPIb-IX-V complex [22]. Mutations leading to
have failed. Used in combination with anti-fibrino- absent expression or dysfunction have been uncov-
lytics, minor bleeding can be controlled in certain ered in the genes for GPIb and GPIX [22]. BSS is
patients. This treatment is often used prior to platelet nearly always inherited in an autosomal recessive
transfusion to avoid blood product exposure and pattern, with consanguinity a frequent finding. The
isoimmunization. platelets are decreased in number and very large on
Finally, in life-threatening bleeding, platelet trans- the peripheral smear. Of note, some patients with
fusions will correct the bleeding defect in most cases, DiGeorge syndrome are missing the GPIb b chain,
even if only one single-donor apheresis unit is given. resulting in large platelets and mild thrombocytope-
Apheresis units (approximately equivalent to six nia, but there is minimal to no functional defect in
pooled blood bank units) are strongly recommended these patients.
and preferred to minimize multiple donor exposure,
which can result in sensitization and a platelet Clinical manifestations. Clinically, BSS typically pre-
refractory state. To minimize long-term sensitization sents in infancy with purpura, epistaxis or gingival
to HLA class I proteins expressed on platelets, the bleeding. The age of onset is related to the severity of
blood products should always be leuko-poor or the disease. Later symptoms can include menorrha-
leuko-depleted. In syndromes with complete absence gia, gastrointestinal or genitourinary bleeding. Trau-
of a membrane GP such as GT or BSS, one should ma or surgical procedures can also lead to excessive
avoid excessive exposure to normal platelets because bleeding. The severity of bleeding symptoms can vary
of the risk of developing an isoantibody to the greatly among patients.
missing proteins of the receptor complex. Isoimmu-
nization appears to be rare in Glanzmann, but the Diagnosis. One should start with a careful family
risk of alloimmunization is still a major concern. history, including consanguinity and bleeding symp-
When it does occur, an isoantibody may be directed toms. Laboratory findings include mild thrombo-
against a functionally important region of the recep- cytopenia but with much more severe bleeding than
tor complex, making subsequent transfusion of one would expect for the relatively small decrease in
normal platelets ineffective. These isoantibodies are count. In type 1 BSS, the patients will also have
distinct from alloantibodies, which are formed to giant platelets on peripheral blood smear [23,24].
more subtle differences in the protein sequence, such A hallmark of the disease is the failure of platelets to
as HPA-1 (PlA1), where the membrane protein is still agglutinate in the presence of ristocetin. This will
otherwise fully expressed and functional. These differentiate BSS from other rare macrothrombocy-
antibodies to normal platelets or HLA Class I have topenic disorders, such as the MYH-9 family of
the potential of making the patient completely platelet disorders. Lastly, flow cytometry should be
refractory to all future transfusions and, in the case performed with antibodies specific for each compo-
of platelet directed antibodies, interfering with suc- nent of the complex (CD 42a-d) to characterize the
cessful bone marrow transplantation for those decrease in the GPIb-IX-V membrane receptor. There
patients even with an HLA matched donor. is also a variant type BSS, in which the GPIb complex
is dysfunctional with poor or absent binding of VWF,
but there is still some complex present on the surface
Bernard–Soulier syndrome
of the platelet. Patients with type 2 BSS may have
Summary. Bernard–Soulier Syndrome (BSS) is a normal platelet size and number [24]. These patients
membrane receptor defect demonstrated to impact are identified by measuring the decreased amount of
the initiation or adhesion phase of platelet plug radiolabelled VWF binding in the presence of rist-
formation and was initially described in 1948. The ocetin cofactor compared with normal platelets.
prominent member of the complex, GPIb, is a
heterodimer composed of disulfide-bonded GPIba Treatment. Significant bleeding or surgical proce-
and GPIbb subunits. GPIb then forms a non-covalent dures may require platelet transfusions. Given the
complex with two GPIXmolecules. Two of these absence of the GPIb-IX complex in BSS patients, the

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PLATELET DEFECTS 1245

risk of sensitization has to be considered. This can Pathophysiology. Megakaryocytes show defective
become a life-threatening complication because a-granule production, with impaired uptake and
future platelet transfusions may be rendered useless storage of endogenously synthesized proteins, such as
by antibodies binding to the GPIb-IX-V complex on platelet factor 4, b-thromboglobulin or VWF, and
transfused platelets. In addition, leucodepleted plate- defective storage of exogenous proteins, such as
lets are required to decrease the exposure to HLA fibrinogen, albumin or factor V. These are key
Class I antigens . Desmopressin and rFVIIa can be components in local platelet interaction and throm-
useful as well, but platelet transfusion remains the bin generation. It is most widely believed that the
mainstay in treatment of severe bleeding. Because primary molecular defect in GPS occurs during the
BSS has a wide clinical spectrum, the prognosis of earliest stages of megakaryocyte maturation and
BSS is related to the severity of an individualÕs disease involves a defect in the packaging of a-granule
and may change overtime based on hormonal alter- contents. Components of the a-granule contents and
ations and the effects of aging. a-granule membrane, including P-selectin, have been
found free in GPS platelet cytoplasm, indicating a
failure of packaging [28].
Storage pool disease
Summary. Storage pool disease (SPD) is a hetero- Clinical manifestations. Bleeding symptoms may start
geneous group of congenital disorders that have in from infancy, but the disease in GPS patients is
common a deficiency of granules, or their consti- usually less severe in general. Easy bruising, pete-
tuents, that results in a defect in ADP release chiae, mucosal membrane bleeding and postsurgical
from activated platelets and abnormal secretion- or traumatic bleeding may occur; life threatening
dependent platelet aggregation [25]. The extension spontaneous haemorrhage is rare.
phase of clot formation and platelet activation is
mediated in large part by the release of stored Diagnosis. Peripheral blood Wright–Giemsa smear
compounds from platelet granules. The principal typically reveals mild to moderate thrombocytopenia
types of platelet granules are the a-granule and the and large gray agranular platelets. Platelet aggrega-
d-granule (dense body). The a-granule contains tion studies are variable with no classical response
numerous proteins involved in platelet interaction, pattern to ADP, epinephrine, thrombin or collagen.
coagulation factors and proteins important in In general, the secretion dependent aggregation
fibrinolysis [26]. The d-granule contains primarily studies are abnormal, but there are some patients
calcium, adenosine triphosphate, ADP and pyro- who also show decreased response to thrombin or
phosphate. It is the presence of the high concentra- collagen [26]. Measurement of platelet adenosine
tion of calcium in the d-granule that gives its dense nucleotide (ADP and ATP) content and release are
appearance on electron microscopy and allows it to useful in the diagnosis of storage pool and release
be distinguished from the a-granule. Defects that defects [29]. When available, a primary tool used in
affect the a-granule are termed a-SPD, those that diagnosis is electron microscopy, which reveals a
affect d-granules are d-SPD and combined defects near complete absence of a-granule in platelets and
are termed ad-SPD [27]. megakaryocytes [30].

a-Storage pool disease (a-SPD) or gray platelet d-Storage pool disease (d-SPD)
syndrome
Summary. Dense granule storage pool defects were
Summary. First described by Raccuglia in 1971, initially described in 1972 [31]. The platelets are
Gray platelet syndrome (GPS) is a deficiency in the morphologically normal on Wright-stained smears,
number of a-granules and their contents in the but they are deficient in dense bodies by electron
platelet cytoplasm of affected patients. Absence of microscopy. These granules are storage sites for
these granules results in a pale or ÔgreyÕ hue on the serotonin and the nucleotides ADP and ATP.
peripheral smear. GPS is thought to be extremely
rare, with approximately 100 cases worldwide. The Pathophysiology. d-SPD patients lack platelet dense
clinical manifestations of bleeding in GPS patients granules resulting in a deficiency of ADP, ATP and
are because of a lack of these a-granule components serotonin, which when released, enhance platelet
resulting in a small and fragile platelet plug. GPS is aggregation. The concentration of ADP correlates
inherited in an autosomal dominant or recessive best with bleeding time and is likely mediated by its
pattern. effect on VWF- and fibrinogen-dependent platelet

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1246 D. SIMON et al.

aggregation via the GPIIb–IIIa receptor. d-SPD is have cytoplasmic inclusions in other cell lines, which
likely inherited in an autosomal dominant pattern but can be easily seen on the peripheral smear. These
neither the gene nor the molecular basis is known. patients exhibit the same findings on platelet aggre-
gation studies as in isolated d-SPD, but in the
Clinical manifestations. d-SPD patients have a bleed- accelerated phase of the disease, they develop
ing spectrum and severity similar to those with thrombocytopenia distinguishing them from milder
a-SPD, including easy bruising, epistaxis and post- disorders. Bleeding symptoms are similar to isolated
surgical bleeding. d-SPD and can be managed accordingly, but only
haematopoietic stem cell transplantation has been
Diagnosis. The diagnosis of d-SPD is made using a shown to improve the long-term outlook of this
combination of techniques. On peripheral blood otherwise fatal syndrome [36].
smear, the platelet number is adequate and platelets
appear normal in structure. A lack of dense granules
ad-SPD
can be better documented using transmission elec-
tron microscopy or fluorescent microscopy using Briefly, combined a and d platelet granule deficien-
special stains [32,33]. Recently, defects in adhesion cies are significantly less common than isolated
under high shear and generation of the prothrom- defects. In these defects, d-granules are always
binase activity have also been reported in patients decreased, whereas the concentration of a-granules
with d-SPD, apparently as a result of decreased ADP varies. These disorders also do not affect the entire
secretion [6]. Platelet aggregation studies typically platelet population uniformly because some platelets
show a significantly impaired second wave of aggre- may have significantly more a and/or d-granules than
gation when stimulated by ADP, epinephrine or other platelets in the same patient. Unlike d-SPD,
thrombin. The most consistent finding is that adenine laboratory testing reveals impaired primary aggrega-
nucleotides are reduced with an increased ratio of tion in addition to secondary aggregation. Clinically,
ATP to ADP and normal levels of lysosomal enzymes these patients behave much like a- or d-SPD patients
[34]. The combination of these findings with a and respond to the same treatments in limited
clinical suspicion leads to the diagnosis of d-SPD experience. Because of the lack of specificity of
[6,32–34]. aggregation studies, the diagnosis also requires
measurement of a- and d-granule contents and/or
electron microscopy to confirm the absence of
d-SPD associated disorders
platelet granules [37].
There are several disorders that have platelet dense
granule deficiency in association with lysosme related Management. The general treatment guidelines listed
organelles as part of their constellation of findings. above are useful but vary from patient to patient in
Most notable is a melanosomal defect which results effectiveness. When bleeding occurs, treatment may
in a pattern of hypopigmentation. The best known include topical agents, DDAVP or Stimate nasal
are Hermansky–Pudlak syndrome (HPS) and related spray for responsive patients and antifibrinolytic
Griscelli syndromes, and Chediak–Higashi syndrome agents. Initial treatment should include regular visits
(CHS) [35]. with healthcare team to be sure that proposed
HPS is an autosomal recessive disorder character- regimens provide hemostasis. In addition, the platelet
ized by oculocutaneous albinism, lysosomal granule transfusions may help for planned surgery, particu-
defects and platelet dense granule deficiency. These larly for the ophthalmologic procedures in CHS, but
patients experience a variety of ocular manifestations this modality has not been studied systematically in
and well-documented pulmonary fibrosis likely sec- SPD or GPS patients.
ondary to the lysosomal defects. From a haemato-
logical standpoint, these patients have a similar
Membrane receptor disorders affecting the stages of
bleeding diathesis as patients with isolated d-SPD.
clot formation
The results of their platelet aggregation studies will
be abnormal in the secondary phase and secretion An evolving area of research is the field of
studies will be abnormal [6,32,33]. inherited disorders of platelet membrane receptors
CHS is also characterized by oculocutaneous affecting platelet extension and cohesion/aggrega-
albinism and dense granule deficiency, but, in addi- tion activities. These disorders include the P2Y
tion, features immune deficiency and a progressive class of receptors, which respond to the adenine
neurological deterioration. CHS patients, moreover, nucleotides secreted by platelet d-granules, as

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PLATELET DEFECTS 1247

well as the TXA2 receptor and the epinephrine Table 2. Classification of Glanzmann thrombasthenia.
receptor. Glycoprotein Fibrinogen Clot
The most studied of these receptors is the P2Y12 IIb–IIIa binding retraction
receptor which is responsible for ADP-induced Type 1 <5% Absent or Absent
platelet aggregation [38]. Defects in P2Y12 are severely deficient
inherited in an autosomal recessive pattern and can Type 2 10–20% Present Normal or
result from a number of different alterations in the moderately deficient
gene coding for the receptor. Clinically, these Variant >50% Variable Variable
patients exhibit a number of the same mild bleeding
tendencies as SPD patients and, on laboratory
workup, are found to have a very weak primary Molecular basis. GT results from either a qualitative
phase of aggregation when stimulated with ADP and or quantitative defect of platelet GPIIb–IIIa com-
other agonists. Only high concentrations of thrombin plex. The genes coding for GPIIb and GPIIIa are
produce normal aggregation studies. These patients located nearby on the long arm of chromosome 17.
generally are treated with DDAVP for prophylaxis or More than 100 mutations have been identified that
bleeding episodes. either inhibit synthesis of the receptor altogether or
interfere with its ability to be processed normally
[39,40]. Genetic testing can be performed in special
Glanzmann thrombasthenia (GT)
academic laboratories to determine the exact
Summary. Recognized first in 1918, GT has been location of the mutation, but on a research basis
extensively studied and defines a defect in the only at this point. (http://sinaicentral.mssm.edu/
consolidation phase of thrombus formation. GT intranet/research/glanzmann).
patients have either a qualitative or quantitative
disturbance in the platelet membrane GPIIb–IIIa Clinical manifestations. Overall, three types of GT
complex. GT is a rare disorder and is inherited in an have been recognized based on the level of expression
autosomal recessive fashion. Consanguinity has been of GPIIb–IIIa (see Table 2).
identified in most cases. Patients with type 1 express <5% of the normal
amount, whereas patients with type 2 express 5%
Pathophysiology. The GPIIb–IIIa receptor is integral to 20%. Heterozygotes express 50% of normal and
to platelet aggregation because in its activated state, are typically asymptomatic, whereas patients with
it preferentially binds to fibrinogen and VWF. type 2 may have a severe phenotype. On the basis
Fibrinogen and VWF then cross-link platelets by of these data, it seems that some level between 20%
binding to the activated GPIIb–IIIa molecule on and 50% is needed to prevent bleeding. Unlike
adjacent platelets. GT platelets are able to adhere many of the other platelet defects, the bleeding from
with other receptors, such as GPIb-IX-V complex, to GT can be severe and may rarely result in death if
exposed subendothelium in damaged capillaries, but not treated appropriately. Bleeding symptoms
are unable to spread effectively without GPIIb–IIIa usually start in early infancy and include epistaxis,
and cannot form platelet microthrombi because of oral bleeding and purpura. The onset of menarche is
their impaired aggregation. associated with severe menorrhagia, often requiring
transfusions. Bleeding symptoms in GT patients are
Diagnosis. GT patients have normal numbers of usually worse in childhood, particularly epistaxis,
platelets that appear morphologically normal on but improve with age [40]. Antibodies against
peripheral blood smear. Screening coagulation GPIIb–IIIa and HLA Class I have been detected in
studies i.e. Protime and aPTT are unaffected, but multiply transfused patients and cause serious com-
bleeding time is prolonged. The typical pattern of plications if the patient becomes refractory to
platelet aggregation studies shows poor aggregation platelet transfusions.
in response to ADP, collagen, epinephrine and
thrombin, but normal aggregation in the presence Management. Localized bleeding can usually be
of ristocetin. If GT is suspected, flow cytometry treated with topical thrombin or antifibrinolytic
can be performed to confirm the diagnosis by agents, but invasive procedures usually require
determining the quantity of GPIIb–IIIa expressed prophylactic platelet transfusion. Childbirth also
on the platelet membrane using specific anti- requires aggressive management with platelet
bodies binding to either GPIIIa (CD61) or GPIIb transfusion both during and after delivery [14].
(CD 41). HLA-matched platelets should be used if possible.

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Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 1240–1249
1248 D. SIMON et al.

Recombinant factor VIIa has been used with success 6 Weiss HJ, Lages BA. Platelet prothrombinase activity
in some patients with alloantibodies or in an effort to and intracellular calcium responses with storage pool
avoid platelet exposure in the first place. Allogeneic deficiency, glycoprotein IIb–IIIa deficiency, or impaired
bone marrow transplantation has been used success- platelet coagulant activity – a comparison with Scott
Syndrome. Blood 1997; 89: 1599–611.
fully in the most severe of cases [41].
7 Salles II, Feys HB, Iserbyt BF, De Meyer SF,
Vanhoorelbeke K, Deckmyn H. Inherited traits affect-
Prognosis. Generally with aggressive supportive care, ing platelet function. Blood Rev 2008; 22: 155–72.
GT patients have a good prognosis. Like many other 8 Zwaal RF, Comfurius P, Bevers EM. Scott Syndrome, a
platelet disorders, poor outcomes have most often bleeding disorder caused by defective scrambling of
been attributed to posttraumatic or unanticipated membrane phospholipids. Biochim Biophys Acta 2004;
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9 Albrecht C, McVey JH, Elliott JI et al. A novel mis-
sense mutation ibn ABCA1 results in altered protein
Summary trafficking and reduced phosphatidlyserine transloca-
The most severe forms of platelet dysfunction are tion in a patient with Scott Syndrome. Blood 2005;
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10 George JN, Caen JP, Nurden AT. Glanzmann
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Disclosures two surveys of the North American Specialized
The authors stated that they had no interests which Coagulation Laboratory Association. Thromb Hae-
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Journal compilation Ó 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 1240–1249