Progress in the Understanding of Sticky Platelet Syndrome

Abstract

The knowledge on the etiology of thrombosis has increased tremendously over the past decades. Nevertheless, Virchow triad is still traditionally invoked to explain mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Recent decades have been focused primarily on describing abnormalities in blood composition, including defects of coagulation proteins and platelets. Although defects of coagulation factors are relatively well-described in the literature, prothrombotic platelet disorders are still less understood. One such defect, the Wien-Penzing defect was first described in 1991. Another platelet defect is sticky platelet syndrome (SPS). In this article, we review information about SPS, and we propose a new definition and standardization of diagnostic criteria. We also attempt to explain the causes and consequences of this condition.
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Full text

Progress in the Understanding of Sticky Platelet
Syndrome
Juraj Sokol, MD,PhD1Maria Skerenova, MSc2Zuzana Jedinakova, MD, PhD1Tomas Simu rda, MD1
Ingrid Skornova, MA, PhD1Jan Stasko, MD, PhD1Peter Kubisz, MD, DSc1
1Department of Haematology and Transfusiology, National Centre of
Haemostasis and Thrombosis, Jessenius Faculty of Medicine in
Martin, Comenius University in Bratislava, Martin, Slovakia
2Department of Biochemistry, Jessenius Faculty of Medicine in Martin,
Comenius University in Bratislava, Martin, Slovakia
Semin Thromb Hemost
Address for correspondence Juraj Sokol, MD, Department
Haematology and Transfusiology, National Centre of Haemostasis and
Thrombosis, Jessenius Faculty of Medicine in Martin, Comenius
University in Bratislava, Kollarova 2, 036 59 Martin, Slovakia
(e-mail: juraj.sokol@me.com).
Platelet hyperaggregability triggered by low concentrations of
platelet agonists adenosine diphosphate (ADP) and/or epineph-
rine (EPI), referred to as sticky platelet syndrome (SPS), was first
described by Holiday at the Ninth Conference on Stroke and
Cerebral Circulation held in Phoenix, Arizona, in 1983.1Since its
first description, several authors have published their experience
with the syndrome. In databases of medical literature (PubMed
and Scopus), almost 50 articles that have focused on SPS have
been indexed by the end of 2015 (searched terms: “sticky
platelet syndrome,”“platelet hyperaggregability”).2–48 Never-
theless, this disorder is still ignored by many researchers. But
this disregard has logical explanations. First, the definition of SPS
does not reflect the latest research discoveries. Second, labora-
tory evidence of platelet hyperaggregability is not standardized.
Third, all researchers trying to find a single cause of this disorder
have failed to do so. The aim of this article is to not only review
the latest knowledge on SPS, but also to attempt to newly define
SPS, to standardize the laboratory and clinical diagnostic proce-
dures and to explain the potential causes of this condition.
Definition
The foundation for the initial definition of SPS was laid by
Mammen and Bick in 1983 and 1984.1,5 SPS was defined as a
platelet disorder with autosomal-dominant trait, characterized
by an increased in vitro platelet aggregation in response to low
concentrations of ADP and/or EPI. Aggregation with other
inducers (collagen, arachidonic acid, ristocetin, and thrombin)
remains normal. However, after 30 years of research, it is
necessary to modify this definition. As discussed later, SPS has
a multifactorial etiology in which genetic and environmental
factors play a role. In addition, this syndrome is characterized by
the composite set of laboratory and clinical signs.
Therefore, SPS should be considered as a multifactorial
qualitative platelet disorder characterized by the occurrence
of venous or arterial thrombosis, migraine, graft versus host
(GVHD) or pregnancy complications, in the presence of in
vivo permanent enhanced platelet aggregation following low
concentrations of ADP and/or EPI. Aggregation in response to
Keywords
►hyperaggregability
►multifactorial
►platelet
►thrombosis
Abstract The knowledge on the etiology of thrombosis has increased tremendously over the past
decades. Nevertheless, Virchow triad is still traditionally invoked to explain mechanisms
leading to thrombosis, alleging concerted roles for abnormalities in blood composition,
vessel wall components, and blood flow in the development of arterial and venous
thrombosis. Recent decades have been focused primarily on describing abnormalities in
blood composition, including defects of coagulation proteins and platelets. Although
defects of coagulation factors are relatively well-described in the literature, prothrom-
botic platelet disorders are still less understood. One such defect, the Wien–Penzing
defect was first described in 1991. Another platelet defect is sticky platelet syndrome
(SPS). In this article, we review information about SPS, and we propose a new definition
and standardization of diagnostic criteria. We also attempt to explain the causes and
consequences of this condition.
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Guest Editors: Emmanuel J. Favaloro,
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Lippi, MD.
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DOI http://dx.doi.org/
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ISSN 0094-6176.

other reagents (collagen, arachidonic acid, ristocetin, and
thrombin) remains normal.
Diagnostic Criteria
SPS has long been definedonlybythelaboratoryresultsof
aggregation testing. The laboratory criteria were first published
in 1988 by Mammen et al.7However, this methodical approach
is no longer valid. We know that platelet aggregability is greatly
affected by preanalytical issues and therefore interpretation of
platelet hyperaggregability is potentially adversely influenced.
Moreover, such interpretations are also strongly influenced by
the potentially high-interlaboratory test variability. The only
way to avoid this problem of interpretation is to standardize the
method for measuring aggregation.
Our recommendations for the standardization of aggreg-
ometry are based on guidelines recently published by the
International Society on Thrombosis and Haemostasis and
British Society for Haematology.49,50 We highly recom-
mended the use of only light transmission aggregometry
(LTA), which is still regarded as the gold standard for testing
platelet aggregation. LTA has been used in most published
studies on SPS.2–48 The samples for platelet function testing
should only be collected from fasting and resting subjects
who have refrained from smoking and caffeine ingestion on
the day of testing. We do not recommended performing LTA
in pregnant women because normal pregnancy is character-
ized by an increase in platelet aggregation and a decrease in
the number of circulating platelets with gestation.51 There
should be a detailed drug history taken before blood collec-
tion. Effects of drugs on the aggregation should be checked in
summaries of product characteristics. Herbal remedies, gar-
lic, alcohol, and certain foods may also cause acquired platelet
dysfunction.52 It is difficult to avoid some of these patient-
related variables, and so if the results of LTA are abnormal,
testing should be repeated within 4 to 6 weeks. Close atten-
tion must be paid tob lood drawing, which should be collected
by experienced phlebotomists using a standardized, atrau-
matic protocol, from the antecubital fossa, by clean venipunc-
ture using minimum tourniquet pressure. Needles should be
in the range of 19 to 21 gauge. We recommend use of
evacuated blood tube systems, where tubes with a variety
of anticoagulant types are required, the citrate tubes should
be collected before EDTA- or heparin-containing tubes wher-
ever possible to avoid the potential for carryover.53 Blood
samples should be drawn into plastic tubes with sodium
citrate and buffered anticoagulant, which help keep the pH
stable during blood processing and testing. Venous blood
should be collected into 0.109 M (3.2%) citrate in a ratio of 1:9
(one part anticoagulant to nine parts blood). The specimens
should be maintained at room temperature. Immediately
after blood collection, all tubes should be mixed by gentle
inversion at least six times (and any tubes discarded if there is
any evidence of clotting). Tubes should be not subjected to any
vibration, shaking, vortexing, continuous mixing, or agita-
tion. The time delay between collection, transport, and
analysis should be b etween 30 minutes and 2 h ours. A platelet
count should be determined before the measurement of
platelet aggregation. The number of platelets should be
within the normal range, that is, from 150 to 350 10
9
/L.
Citrated blood samples obtained as described above are
centrifuged to prepare platelet rich plasma (PRP) and platelet
poor plasma (PPP). To prepare PRP, whole blood tubes should
be centrifuged at 170 to 200 g for 10 minutes in a swingout
rotor. Autologous PPP is prepared by centrifugating blood at a
minimum of 1,500 g for at least 15 minutes. At the end of the
centrifugation steps a plastic pipette should be used to
separate the top two-thirds of PRP or PPP, which should be
carefully removed without di sturbing the buffy coat layer and
red cells. The PRP should then be left for at least 30 minutes
before testing. Visual inspection of samples is important, as
icteric, lipemic, red cell contaminated, and hemolysed sam-
ples should not be tested.54,55 It is important that samples are
preincubated for at least 5 minutes at 37°C before assay to
obtain stable baseline traces. The appropriate agonists must
then be added directly to the PRP and not pipetted onto the
side of the tube. It is important that no air bubbles are
introduced at any stage of the procedure as these can inter-
fere with transmission measurement. The aggregation trac-
ing should be observed for at least 5 minutes, but preferably
10 minutes, to monitor the lag phase, shape change, primary
and secondary aggregation, and any delayed platelet
responses (e.g., reversible or spontaneous aggregation). It is
recommended that local, normal cutoff values are estab-
lished, using nonparametric statistics. Each sample should
be tested with three low concentrations (final concentration
in the PRP cuvette) of ADP (2.34 µmol/L, 1.17 µmol/L, and 0.58
µmol/L) and EPI (11.0 µmol/L, 1.1 µmol/L, and 0.55 µmol/L). As
mentioned above, if the results are abnormal, tests should be
repeated. The diagnosis is confirmed if:
1. Clinical symptoms of SPS are present and hyperaggreg-
ability to two or more concentrations of either reagent is
determined
2. Clinical symptoms of SPS are present and hyperaggreg-
ability to one or more concentrations of both reagents is
determined
Classification
According to the aggregat ion pattern, SPS is classified a s type I
(hyperaggregation after both ADP and EPI), type II (hyper-
aggregation after EPI alone), or type III (hyperaggregation
after ADP alone). SPS type II seems to be the most common
form in the White population. Type III is very rare.1,5 On the
contrary, type I is most common in Mexican mestizos.15 It is
important to stress that this classification is based on labora-
tory testing and has no relation to the clinical features,
prognosis, or management of patients, and no prominent
clinical and therapeutic differences have been seen among
the types to date.40
Clinical Presentation
Clinical symptoms of SPS include venous or arterial throm-
bosis, migraine, GVHD, and pregnancy complications. The
total number of patients with SPS examined in the Slovak
Seminars in Thrombosis & Hemostasis
Progress in the Understanding of Sticky Platelet Syndrome Sokol et al.

National Centre of Haemostasis and Thrombosis is presented
in ►Table 1. We examined 1,800 patients with suspected SPS
(patients with history of unprovoked thrombosis, migraine,
and fetal loss syndrome) over the past 11 years. We have
confirmed the diagnosis of SPS in 360 (20%) patients. Arterial
thrombosis was the most common event (n¼159, 44%).
Venous thrombotic events occurred in 127 patients (35%),
migraine in 20 (1.1%) patients, and fetal loss syndrome in 54
(3%) patients. There were 41% patients with SPS who were
younger than 40 years.
In the literature review, arterial thrombosis is the most
common clinical manifestation of the syndrome. According to
Mammen et al, SPS can even be regarded as the most frequent
cause of unexplained arterial thrombosis.7The common
localization of arterial thrombosis is in coronary or cerebral
arteries.5,6 However, SPS may also lead to thrombosis devel-
oped in the atypical sites of the circulation. Several cases of
retinal vascular thrombosis,21,22,27 thrombosis of cerebral
sinuses11 or peripheral and visceral arterial thromboembo-
lism26,29 have been reported.
Venous thrombosis is the second most common clinical
manifestation of SPS. In 1998, Bick was among the first to
describe SPS in patients with venous thrombosis.9He began
testing for SPS in 1995 and in 2 years 153 patients with
unexplained arterial and venous thrombotic events were stud-
ied. A total of 21% patients with unexplained arterial events had
SPS and 13.2% patients with unexplained venous thrombosis
hadSPS.Inaddition,unexplainedarterialandvenous throm-
botic events, commonly occurring in stressful situations, were
frequently recurrent in SPS patients while under oral anticoag-
ulant therapy.5,9,15 The first arterial or venous thrombotic event
typically occurs in rather young SPS patients, often during the
third and fourth decade of life and sometimes even in childhood.
Affected individuals are usually without or have only mild
acquired risk factors for thrombosis that do not correspond
with the clinical severity of the event.40
In women, SPS often occurs during pregnancy and is associ-
ated with complications related to impaired placental vasculari-
zation, such as intrauterine growth retardation or fetal loss.40
Bick and Hoppensteadt showed that a significant number of
women with recurrent miscarriage (18.2% of 351 tested individ-
uals) fulfilled the criteria of SPS. They thus provided a strong
clinical evidence for the relation of SPS to fetal loss.19
Several authors have published cases and patient cohorts
with SPS and migraine.10,21,56,57 It seems that SPS is rarely the
cause of a migraine. However, SPS may be the only thrombo-
philic state responsible for the development of migraine
associated with aura.57
El-Amm et al,24 Mühlfeld et al,23 and Yagmur et al58
described platelet hyperaggregability in patients undergoing
hemodialysis or renal transplant recipients with thrombotic
complications or impaired function of the graft. The results of
Yagmur et al58 are particularly worth mentioning. They
evaluated platelet aggregation after EPI in 30 hemodialysis
patients and 34 renal transplant recipients and found a high
prevalence of SPS.
Prevalence
Although several reports on SPS have been published to date,
the epidemiological data are limited. The prevalence of SPS in
the general populati on is not known. Similarly, the prevalence
in patients with history of thrombosis cannot be assessed
because all published studies with relevant number of par-
ticipants examined only selected subpopulation (e.g., only
those with unexplained thrombosis).9,10 Bick, in the cohort of
195 patients with unexplained thrombosis, found SPS in
17.6% of the cases.9Andersen found SPS in 56 (28%) of 195
selected patients with history of unexplained thrombosis.13
Our group found 20% SPS patients in our own cohort group
(see ►Table 1). Furthermore, Bick et al discussed the rela-
tionship between SPS and recurrent miscarriages (64 SPS
Table 1 Patients with sticky platelet syndrome as diagnosed by the National Centre of Haemostasis and Thrombosis, Slovakia
Patients’characteristics Tested patients/sticky platelet syndrome 1,800/360
Gender, male/female 112/248
Mean age (range), y 47.5 (0–72)
Type of sticky platelet syndrome Type I 80
Type II 277
Type III 3
Clinical manifestation Venous thrombosis
Deep vein thrombosis 85
Pulmonary embolism 42
Arterial thrombosis
Stroke 139
Myocardial infraction 20
Migraine 20
Fetal loss syndrome 54
Seminars in Thrombosis & Hemostasis
Progress in the Understanding of Sticky Platelet Syndrome Sokol et al.

diagnosis among 351 women with miscarriages; 20%),19 as
well as between SPS and recurrent thrombosis in hemodialy-
sis patients (11 of 27 patients; 41%).59 It was also found that
SPS is a very frequent condition in patients with acquired
immune deficiency syndrome receiving antiretroviral thera-
py for at least 6 months and suffering from unexplained
cardiovascular events.60 However, all these results ought to
be assessed cautiously because of the possible selection bias
and different standard conditions for measuring platelet
aggregation.
Pathogenesis of SPS
SPS follows a multifactorial inheritance pattern as both
genetic and environmental factors are involved in its patho-
genesis.45,47 These factors work together in ways that are not
fully understood so far. At present, it can only be assumed that
they cause changes in platelet membrane glycoproteins or
intracellular signal pathways involved in platelet activation
and aggregation.
Most of the genetic studies conducted so far demonstrate
that variability of GP6 (the gene for glycoprotein VI; the main
receptor for collagen63), GAS6 (the gene for GAS6 protein;
enhances platelet reactivity64), and PEAR1 (the gene for
PEAR1 protein; enhances platelet reactivity65) are involved
in the pathogenesis of SPS (see ►Table 2). These studies, as
well as the laboratory heterogeneity of SPS (three different
types), clearly show complex genetics, as also recognized for
some other hemostatic disorders such as some types of von
Willebrand disease, where various mutations of the same or
even other genetic loci can result in similar phenotypes.42
Furthermore, it is important to emphasize that platelet hyper-
aggregability to nat ural agonists (including EPI and ADP) with
consequent increased risk of thrombosis has been described
Table 2 SPS genetic studies
Author Cohort Gene/polymorphism Results
Kubisz
et al, 200634 Nine white SPS patients with
unexplained thrombosis
Male:4;female:5
Type I: 2; type II: 6; type III: 1
GPIIIa/rs5918 No clear relation between SPS and
polymorphism
Kubisz
et al, 201035 128 white SPS patients (42 men and 86
women) with unexplained arterial or
venous thrombosis vs. 137 control
subjects(67menand70women)
Type I: 35; type II: 91; type III: 2
Whites
GAS6/rs8191974 No clear relation between SPS and
polymorphism (rs8191974 more
frequent in patients with SPS type II)
Ruiz-Argüelles
et al, 201237 95 Mexican mestizo SPS patients
(43menand52women)witharterial
or venous thrombosis or with family
history of thrombosis or recurrent
abortion versus 127 control subjects
Type I: 61; type II: 6; type III: 28
GPIIIa/rs5918 No clear relation between SPS and
polymorphism
Kubisz
et al, 201238 71 white SPS patients with history of
stroke(24menand47women)vs.77
control subjects (35 men, 42 women)
Type I: 17; type II: 52; type III: 2
GP6/rs1654410, rs1671153,
rs1654419, rs11669150,
rs1613662, rs12610286,
rs1654431
No clear relation between SPS and
polymorphisms (rs12610286 more
frequent in patients with SPS type I)
Sokol
et al, 201261 27 white SPS patients with history of
fetal loss (27 women) vs. 42 control
subjects (42 women)
Type I: 7; type II: 20; type III: 0
GP6/rs1654410, rs1671153,
rs1654419, rs11669150,
rs12610286, rs1654431
rs1671153 and rs1654419 were
more frequent in patients with SPS
Kotulicova
et al, 201262 77 white SPS patients with history of
venous thromboembolism (28 men
and 49 women) vs. 77 control subjects
(35men,42women)
Type I: 22; type II: 54; type III: 0
GP6/rs1654410, rs1671153,
rs1654419, rs11669150,
rs1613662, rs12610286,
rs1654431
rs1613662 and rs1654419 were
more frequent in patients with SPS
(rs1671153 and rs1654419 were
more frequent only in SPS type II)
Sokol
et al, 201545 27 white SPS patients with history of
fetal loss (27 women) vs. 42 control
subjects (42 women)
Type I: 7; type II: 20; type III: 0
GAS6/rs7400002, rs1803628,
rs8191974, rs9550270
PEAR1/rs12041331,
rs12566888
PEAR1: rs12041331 and
rs12566888 were more frequent in
patients with SPS
GAS6: rs9550270 was more
frequent in patients with SPS
Sokol
et al, 201547 27 white SPS patients with history of
fetal loss (27 women) vs. 42 control
subjects (42 women)
Type I: 7; type II: 20; type III: 0
GP6/rs4281840, rs12981732,
rs10417943, rs1671152,
rs1654433, rs1671215,
rs10418743, rs8113032
rs1671152, rs1654433, and
rs1671215 were more frequent in
patients with SPS
Abbreviation: SPS, sticky platelet syndrome.
Seminars in Thrombosis & Hemostasis
Progress in the Understanding of Sticky Platelet Syndrome Sokol et al.

in previous studies in patients with several chronic disorders,
such as complex metabolic (diabetes mellitus and atheroscle-
rosis) and inflammatory (systemic immune diseases)
disorders.42,66,67
Therapy
There are not guidelines for the treatment of SPS. In most
patients with SPS, low doses of acetylsalicylic acid (ASA)
(80–100 mg/day) were clinically efficient and also led to the
normalization of aggregation pattern. In patients who did not
achieve an adequate response to the initial low-dose ASA,
escalation of the dose to up to 325 mg/day was used with
good clinical results. In a small patient group, wherein ASA is
contraindicated or inefficient despite high daily doses, other
antiplatelet drugs (preferably ADP inhibitors) should be
attempted.40 The big challenge remains patients with SPS and
concomitant thrombophilia disorders or pregnant women.
These states lead to the administration of a combination of
antithrombotics (antiplatelet agents with anticoagulants) with
individualized dosing. Antiplatelet therapy is recommended as a
lifelong therapy that should never be interrupted.
Conclusion
SPS is a life-threatening condition. Its timely detection and
subsequent clinical and therapeutic management can save the
life of the patient or their unborn child. Wehope that this article
will generate additional interest in investigators that may even-
tually contribute to the better understanding of the syndrome.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Acknowledgments
The study was suppo rted by grant VEGA 1/0168/16 and th e
project “Increasing Opportunities for Career Growth in
Research and Development in the Field of Medical Scien-
ces,”ITMS: 26110230067, co-funded from EU sources and
European Social Fund.
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