Sticky Platelet Syndrome

Sticky Platelet Syndrome

Peter Kubisz, MD, DSc1 Jan Stasko, MD, PhD1 Pavol Holly, MD, PhD1

1Department of Hematology and Transfusion Medicine, Jessenius

Faculty of Medicine of the Comenius University, University Hospital,

Martin, Slovakia

Semin Thromb Hemost 2013;39:674–683.

Address for correspondence Peter Kubisz, MD, DSc, Department of

Hematology and Transfusion Medicine, Jessenius Faculty of Medicine

of the Comenius University, University Hospital, Kollarova 2, 036 59

Martin, Slovakia (e-mail: [email protected]).

Inherited thrombocytopathies are in general rare diseases.1,2

Historically, the bleeding disorders—Bernard–Soulier syndrome

and Glanzmann thrombasthenia, in particular—were described

first and were the subject of extensive scientific research. In the

past 30 years, however, research has found few disorders, sticky

platelet syndrome (SPS) and Wien–Penizng defect, as well as

platelet glycoprotein polymorphisms, PLA1/2 polymorphism of

humanplatelet antigen 1 (HPA-1) in glycoprotein (GP) IIIa and T-

5Cpolymorphism inGPIb, to be associatedwith an increased risk

of thromboembolism (TE).2–5 Among them, SPS, characterized

by increased in vitro platelet aggregation after activation with

low concentrations of adenosine diphosphate (ADP) and/or

epinephrine (EPI), was most intensively studied.3

Discovery and History of Sticky PlateletSyndrome

SPS was for the first time publicly described as a separate

clinical syndrome by Holiday and associates at the Ninth

International Joint Conference on Stroke and Cerebral Circu-

lation in Arizona in 1983.3 Patients with this disorder were

presented as cases with stroke and platelet hyperaggregabil-

ity after ADP and EPI (►Fig. 1).3 However, the relation

between platelet hyperaggregability and ischemic stroke

was initially recognized by al-Mefty et al in 1979.6 In 1984,

Mammen treated a female patient who suffered from myo-

cardial infarction during the third semester of her first

gravidity and in whom the extensive laboratory testing of

hemostasis revealed no abnormalities except in vitro in-

creased platelet aggregation after ADP and EPI.7 He outlined

the possible genetic cause of the syndrome by emphasizing

the fact that the patient’s mother suffered from myocardial

infarction (MI) during one of her pregnancies and the pa-

tient’s 18-year-old brother had repeated angina pectoris

despite normal angiography of coronary arteries.7 In the

following years, Mammen and associates published their

studies on a larger series of patients, defined generally

accepted laboratory diagnostic criteria, and proposed two

Keywords

► sticky platelet

syndrome

► platelet

hyperaggregability

► thrombophilia

► platelet disorders

Abstract Sticky platelet syndrome (SPS) is a thrombophilic thrombocytopathy with familial

occurrence and autosomal dominant trait, characterized by an increased in vitro platelet

aggregation in response to low concentrations of adenosine diphosphate (ADP) and/or

epinephrine (EPI). According to aggregation pattern, three types of the syndrome can

be identified (hyperresponse after both reagents, Type I; EPI alone, Type II; ADP alone,

Type III). Clinically, the syndrome is associated with both venous and arterial thrombosis.

In pregnant women, complications such as fetal growth retardation and fetal loss have

been reported. The first thrombotic event usually occurs before 40 years of age and

without prominent acquired risk factors. Antiplatelet drugs generally represent ade-

quate treatment. The use of other antithrombotics is usually ineffective and may result

in the recurrence of thrombosis. In most patients, low doses of antiplatelet drugs

(acetylsalicylic acid, 80–100 mg/d) lead to normalization of hyperaggregability.

Combination of SPS with other thrombophilic disorders has been described. Despite

several studies investigating platelet glycoproteins’ role in platelets’ activation and

aggregation, the precise defect responsible for the syndrome remains unknown. The

aim of this review is to summarize authors’ own experience about SPS and the clinical

data indexed in selected databases of medical literature (PubMed and Scopus).

published online

August 9, 2013

Issue Theme Rare Bleeding Disorders:

Genetic, Laboratory, Clinical, and

Molecular Aspects; Guest Editor, Maha

Othman, MD, PhD

Copyright © 2013 by Thieme Medical

Publishers, Inc., 333 Seventh Avenue,

New York, NY 10001, USA.

Tel: +1(212) 584-4662.

DOI http://dx.doi.org/

10.1055/s-0033-1353394.

ISSN 0094-6176.

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http://dx.doi.org/10.1055/s-0033-1353394

http://dx.doi.org/10.1055/s-0033-1353394

types (I and II) of the syndrome.7–10 In the mid-1990s, on the

basis of the analysis of his own patient cohort, Bick added

another type (III) of the syndrome.11 Subsequently, several

authors published other cases and patient cohorts with the

syndrome and its various clinical manifestations: coronary

syndromes,migraine, idiopathic optic neuropathy, venous TE,

and fetal loss syndrome.12–34 In the late 2000s, Mühlfeld

et al25 and El-Amm et al26 regarded the syndrome as a

possible cause of thrombotic complications and impaired

function of the graft in kidney transplantation. Also, recently

two family studies, providing the evidence for the familiar

occurrence and the possible genetic background of the syn-

drome, were reported.34,35 Throughout the years, several

studies focused on the etiology and pathogenesis of the

syndrome, but they had failed to fully reveal the genetic basis

underlying the syndrome.36–42

Clinical Evidence of Sticky Platelet Syndrome

Since its first description in the early 1980s, several authors

have published their experience with the syndrome. In

respected databases of medical literature (PubMed and Sco-

pus), up to 40 articles that focused on SPS have been indexed

by the end of 2012 (searched terms: “sticky platelet syn-

drome,” “platelet hyperaggregability”).3–40 Studies were

largely nonrandomized and case reports. There were two

retrospective studies, and only six studies analyzed more

than 20 patients. The following description of the syndrome

will be based on the data provided by these studies or

references cited by them (summarized in ►Table 1) as well

as on the data of our own patient cohort (►Table 2). Our

patient group included all patients diagnosed with SPS while

undergoing thrombophilia testing at our department in the

past 8 years and 5 months (period between January 1, 2004,

and May 31, 2012). Altogether, 1,348 patients with TE were

evaluated and 270 patients with SPS were identified.

Almost all studies including our own were performed on

whites and thus the conclusions in this review pertain to this

particular population.

Definition, Classification, and Diagnostics ofSticky Platelet Syndrome

Although usually regarded as an inherited disorder, SPS is

defined by its clinical and laboratory features and not by

genetic testing. At present, the diagnostic criteria proposed

Fig. 1 Platelet aggregation in SPS and healthy individuals. ADP, adenosine diphosphate; EPI, epinephrine; N, normal values (author’s own data);

SPS, sticky platelet syndrome.

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Table 1 Summary of published data on SPS (databases: PubMed and Scopus)

References No. of cases Age, y SPS type Clinical manifestation Family historyfor TE/SPS

Other risk factorsfor TE

Treatment(dose in mg/d)

Rubenfire et al8 27 48 NR 41 angina pectoris withnormal angiography ofcoronal arteries

NR NR NR

Mammen et al9 34 9–51 3, I; 31, II 6 TIA, 28 stroke Positive in 26 Smoking in 10 NR

Mammen et al9 20 34–54 NR 20 idiopathic ischemicoptic neuropathy

NR Smoking (ns) NR

Berg-Dammer et al13 2 43, 52 1, II; 1, I Stroke (1 sinuses) Positive in 1 None ASA þ low-dose VKA(ns); ASA (ns)

Chittoor et al14 1 30 II Stroke (sinuses),recurrent DVT

NR None Heparin, VKA, ASA(325)

Bicka 27 (153 tested) NR NR 11 DVT � PE, 16 AT NR None 29 ASA (81); 1 ASA(325); 1 ticlopidine

Andersen et al15 56 (195 tested) NR NR NR NR in 18 patients (ns) NR

Chaturvedi and Dzieczkowski11,16 1 40 II Recurrent stroke, DVTwith PE

Negative APC-R (FVL hetero-zygote), PSdeficiency

Anti-PLT (ns)

Lewerenz et al19 1 64 II Ulcerations and livedoracemosa, MI, recurrentstroke, peripheralarterial disease

NR APC-R (FVLheterozygote)

Heparin, ASA (100)

Ruiz-Argüelles et al20 22 (46 tested) 24–63 12, I; 4, II; 6, III NR NR 3 APC-R, 5 PT-20210, 5 APS, 2 PSdeficiency, 2 ns

NR

Bick and Hoppensteadt21 64 (351 tested) NR NR Recurrent miscarriage NR NR ASA (81)

Kahles et al22 1 40 I MI, PE NR None Stent, fibrinolytics,LMWH þ antiplateletdrugs (ns)

Fodor et al23 1 25 II AT (carotid, renitalartery), migraine

NR " FVIII:C, oral con-traceptives,smoking

ASA (300, then 100)

Randhawa and Van Stavern24 1 15 NR Nonarteritic anteriorischemic opticneuropathy

Negative None ASA 81

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Table 1 (Continued)

References No. of cases Age, y SPS type Clinical manifestation Family historyfor TE/SPS

Other risk factorsfor TE

Treatment(dose in mg/d)

Mühlfeld et alb 3 18–59 3, II Renal infarction, recur-rent stroke, DVT, PEischemic colitis, graftdysfunction

Positive in 1 None Low-dose ASA (ns);VKA/ LMWH þ

clopidogrel þ ASA (ns);ASA(300)

El-Amm et alb 3 46–55 3, I Recurrent accessthrombosis, recurrentDVT

NR APS, HHC; PS defi-ciency, LE; HHC

LMWH þ ASA (81);VKA/LMWH þ ASA;ASA (325)

Kannan25–27 1 17 II AT (femoral artery),recurrent stroke, MI

Negative None VKA initially, then ASA(ns)

Sand et al28 1 72 II AT, recurrent PE NR Abdominal surgery,active cancer

VKA, heparin

Bojalian et al30 1 48 I AT (renal, splenicartery), stroke, recur-rent thrombosis of theupper extremities

NR APS Thrombectomy, directFII inhibitors (ns)

Loeffelbein et al31 1 56 II Recurrent thrombosisof arterial anastomosisof the free flap

NR Active cancer Low-dose ASA (ns)

Rac et al32 1 NR I DVT during pregnancy,recurrent fetal loss

NR None LMWH

Gehoff et al33 1 56 II Recurrent stroke Positive None Clopidogrel (75),ASA (100)

Guillermo et al34 5 22–56 2, I; 2, III Stroke, DVT, PE Positive in 5 PT-20210, HHC, LA;HHC; HHC; oralcontraceptives;none

Anagrelide; ASA (ns);ASA (ns); ASA (ns); ASA(ns)

Abbreviations: APC-R, resistance to activated protein C; APS, antiphospholipid syndrome; ASA, acetylsalicylic acid; AT, arterial thrombosis; DVT, deep vein thrombosis; F, female; FII, coagulation factor II; FV,

coagulation factor V; FVIII:C, FVIII plasma coagulation activity; FVL, factor V Leiden; HHC, hyperhomocysteinemia; LA, lupus anticoagulants; LE, lupus erythematosus; LMWH, low-molecular-weight heparin; M, male;

MI, myocardial infarction; NR, not reported; ns, not specified; PE, pulmonary embolism; PS, protein S; SPS, sticky platelet syndrome; TE, thromboembolism; TIA, transient ischemic attack; TU, tumor; VKA, vitamin K

antagonists.aRetrospective study of patients with unexplained TE; duplicate studies from the same author groups are not included.bPatients after kidney transplantation.

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by Mammen7 and Bick11 are generally accepted and were

used in all published studies (►Table 3). According to this

criteria, SPS is a thrombophilic thrombocytopathy with fa-

milial occurrence (showing autosomal dominant trait and

affecting both genders), characterized by increased in vitro

platelet aggregation after low concentrations of ADP and/or

EPI. Aggregation in response to other reagents (collagen,

arachidonic acid, ristocetin, and thrombin) remains normal.

According to aggregation pattern, three types of the syn-

drome can be identified (►Table 3).

Type II is most common (hyperaggregability to EPI alone),

followed by Type I (hyperaggregability to ADP and EPI),

whereas Type III (hyperaggregability to ADP alone) is rare.

In our study, Type I was found in 30.0%, Type II in 69.3%, and

Type III in 0.7% of population tested. It is important to stress

that this classification is based on laboratory testing and has

no relation to the clinical features, prognosis, or management

of patients, and no prominent clinical and therapeutic differ-

ences were seen among the types so far.

Platelet aggregation is evaluated by commonly used meth-

ods: optical or impedance aggregometry. Platelet-rich plasma,

obtained from the freshly drawn blood mixed with the appro-

priate anticoagulation reagent (usually 3.2% sodium citrate), is

used for the testing. As a standard, three concentrations of each

reagent are repeatedly tested. Optical aggregometrywas used in

thefirst reports and remainedapreferredoption inmost studies.

The withdrawal of all drugs with possible effect on platelet

function (antiplatelet antithrombotics and nonsteroidal anti-

inflammatory drugs) for an appropriate time (at least 10 days in

case of acetylsalicylic acid [ASA]) and testing at times with no

acute disturbances in hemostasis (at least 3months after the last

thromboembolic event) are necessary for obtaining valid results.

Table 2 Characterization of the authors’ patient cohort

Patients’ characteristics Tested patients/sticky platelet syndrome patients, N/n (%) 1,348/270 (20.0)

Gender, male/female, N/n (%) 83 (30.7)/187 (69.3)

Mean age (range), y 47.5 (9–64)

Sticky platelet syndrome type, n (%) Type I 81 (30.0)

Type II 186 (68.9)

Type III 3 (1.1)

Clinical manifestation, n (%) Asymptomatic (identified in family studies) 2 (0.8)

Symptomatic 268 (99.2)

• Venous thrombosis/pulmonary embolism 94 (34.8)

• Arterial thrombosis 179 (66.3)

○ Stroke 90 (33.3)

○ Coronary syndromes 19 (7.4)

• With both arterial and venous thrombosis 5 (1.9)

Table 3 Classification and diagnostic criteria of sticky platelet syndrome

Platelet aggregation after activation with

ADP EPI

Concentration of reagent, µM 0.58 1.17 2.34 0.55 1.1 11.0

Normal range, % aggregationa 0.0–12.0 2.0–36.0 7.5–55.0 9.0–20.0 15.0–27.0 39.0–80.0

Classification: Sticky plateletsyndrome types

Type I þ þ

Type II – þ

Type III þ –

Diagnostic criteria

Suggestive diagnosis: History of TE and hyperaggregability to only 1 concentration of 1 reagent

Firm diagnosis: History of TE and hyperaggregability to 2 concentrations of 1 reagent

History of TE and hyperaggregability to 1 concentration of both reagents

History of TE and hyperaggregability to only 1 concentration of 1 reagent, repeatedly tested

Abbreviations: ADP, adenosine diphosphate; EPI, epinephrine; TE, thromboembolism; þ, platelet hyperaggregabiliy after at least two low

concentrations of an inducer11; –, platelet aggregation within normal range after all three low concentrations of an inducer.11

aOnly informative, can be different for each laboratory; modified according to the studies by al-Mefty et al6 and Mammen.7


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Etiology of Sticky Platelet Syndrome

On the basis of the initial descriptions and data acquired from

family studies, SPS is regarded as an inherited disorder with

autosomal dominant pattern of inheritance. However, al-

though its phenotype including familiar occurrence is clearly

defined, the exact genetic cause is yet to be found. Mammen

and associates proposed the defect, although not specifically

named, to be in membrane glycoproteins (GPs) involved in

platelet activation and subsequent effects.10 The idea that the

defect lies in platelet activation pathways is supported by the

finding of activated platelets in asymptomatic SPS patients.

The increased surface expression of CD62 (P-selectin) and

CD51—platelet proteins expressed only after their activation

—and measured by flow cytometry was found in SPS patients

in comparison with normal population, even at the time

outside of acute thromboembolic event.38

Because the platelets’ role in blood clot formation require

several GPs, mutations of genes coding for several platelet

proteins could participate in the genetic impairment of

aggregation. The most prominent GPs include GPIa/IIa (inter-

action with von Willebrand factor in adhesion and platelet

activation), GPIb/IX/V and GPVI (interaction with collagen in

adhesion and signal transduction in platelet activation),

GPIIb/IIIa (interaction with fibrinogen in aggregation), pros-

taglandin family receptors, protease-activated receptor class

receptors (thrombin receptors), α2-adrenergic receptors (EPI

receptors), P2Y and P2Y12 (ADP receptors), Gas6 protein

(enhancement of platelet activation by modulating the func-

tion of α2-adrenergic and ADP receptors), and PEAR1 receptor

(signaling on the formation of platelet–platelet contacts sec-

ondary to platelet aggregation).

So far, research had focused on GPIIIa, Gas6, and GPVI

proteins.43 These GPs were particularly interesting because

certain mutations in their genes were shown to modulate the

risk of TE in humans. A2 allele of GPIIIa (PLA A1/A2 polymor-

phism) was associated with an increased risk of cardiovascu-

lar disease and increased in vitro platelet aggregation after

EPI, as shown on 1,422 participants of the Framingham

Offspring Study.44 Allele A of Gas6 c.834 þ 7G > A polymor-

phism was found to be protective for cerebral thrombosis

with decreased prevalence in a subpopulation with stroke.45

Several single nucleotide polymorphisms (SNP) of GPVI were

found to be associated with increased risk of stroke or

myocardial infarction.46–48 The importance of genetic vari-

ability of the GP6 gene for platelet aggregation was stressed

by a recent genome-wide meta-analysis that identified this

gene among seven loci associatedwith platelet aggregation to

physiological agonists.49

Only limited number of studies related to the prevalence of

the defects in SPS patients are available and are summarized

in►Table 4. In general, all the studies have failed to prove any

of thesemutations to be a single genetic defect responsible for

SPS and did not find a consistent relation to SPS and its types.

In a case of GPVI, three SNPs appeared to be more frequent in

patients with SPS (rs1671153, rs1654419, and rs1613662),

particularly among those with SPS Type II and in whom the

syndrome manifested by venous thromboembolism or fetal

loss.41,42 Thus, although these polymorphisms are not the

underlying disorder, but they could have a modulating effect

on the clinical presentation of the syndrome.

The observed discrepancy in genetic studies as well as

laboratory heterogeneity of SPS (three distinct types) might

suggest a multifactorial genetics, as known in 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 the similar phenotype. This idea is

supported byour finding of a higher occurrence of certain alleles

of both GAS6 (rs7400002) and PEAR1 (rs12566888) polymor-

phisms in the same patients with SPS in association with fetal

loss (Peter Kubisz, MD, DSc, Unpublished data, March 2013).

Furthermore, it is important to emphasize that platelet

hyperaggregability to natural agonists including EPI and ADP

with increased riskof TE as a consequencewas described in the

studies on several acquired disorders, such as complex meta-

bolic (diabetesmellitus and atherosclerosis) and inflammatory

(sepsis and systemic immune diseases) disorders.50,51 These

conditions can produce laboratory and clinical signs resem-

bling SPS. Therefore, it is important to clearly distinguish these

patients, especially in pathophysiological studies—a problem

not exhaustingly addressed in all previous analyses. Further

complex studies, which will focus preferably on children and

young adults (with some exceptions, patients not likely to be

affected by aforementioned disorders), are necessary for the

deeper understanding of the syndrome.

Prevalence of Sticky Platelet Syndrome

The prevalence of SPS in the general population is not known

because the performed studies only focused on the subpopu-

lationwith TE. Similarly, the prevalence in this subpopulation

cannot be assessed because all published studies with rele-

vant number of participants examined only selected propor-

tion of these patients—those with unexplained

thrombosis.11,15 In that particular group of patients, SPS

seems to be relatively frequent. Bick in his cohort of 195

patients with unexplained thrombotic event found SPS in

17.6%.11 Andersen found SPS in 56 (28.0%) of 195 selected

patients with TE.15 In our own patient cohort with unex-

plained TE, wewere able to confirm the presence of SPS in 270

(20%) of 1,348 patients. However, these results ought to be

assessed cautiously because of the possible selection bias (for

example, 1,348 patients in our cohort were selected of 5,356

individuals tested for thrombophilia and the selection was

based solely on the treating clinician’s decision and his

satisfaction with the explanation of thromboembolic event).

It is obvious that the prevalence of SPS in the unselected

cohorts of patients with TE or in the general population is

markedly lower. Thus, SPS can be considered an infrequent or

even rare thrombophilic defect in the whites.

Clinical Manifestation and Diagnosis ofSticky Platelet Syndrome

In general, the clinical symptoms of SPS are similar toTE from

other causes. However, certain distinct features could be



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identified in both patient’s personal (time of thrombosis

occurrence, its localization and association with risk factors,

and response to therapy) and family (affected family mem-

bers) history (►Table 5). SPS is diagnosed in patients with

both arterial and venous TE, and it is not unusual to find both

events in one patient or in family pedigree. However, arterial

thrombosis, namely stroke and coronary syndromes, appears

to be more frequent. In his cohort of 195 patients with

unexplained thrombotic event, Bick found SPS in 21.0%

with arterial and in 13.2%with venous TE.11We found arterial

thrombosis in approximately two-thirds of all patients with

SPS (with stroke and coronary syndromes counting for almost

two thirds of arterial events), whereas venous TE was seen in

only 34.4%.

Table 4 Summary of genetic studies in sticky platelet syndrome

Authors Population characteristics Mutation (polymorph-ism) tested

Results

Kubisz et al36 9 patients with SPS (4, M/5, F; 2, TI/6,TII/1, TIII); whites

GPIIIaPlA A1/A2 No clear relation between SPSand SNP

Ruiz-Argüelles et al39 95 patients with SPS (43, M;/52, F; 61,TI/6, TII/28, TIII); 127 controls;Mexican mestizo

GPIIIaPlA A1/A2 No significant differencesbetween SPS and controlgroup

Kubisz et al37 128 patients with SPS (42, M/86, W;35, TI/91, TII/2, TIII); 137 controls;whites

Gas6 c. 834 þ 7G > A No significant differencesbetween SPS and controlgroup; allele G more prevalentin SPS Type II

Kotuličová et al42 77 patients with SPS (VTE; 22, TI/54,TII/1, TIII); 77 controls; whites

6 GP6 SNPs (rs1654410,rs1671153, rs1654419,rs11669150, rs12610286,and rs1654431)

2 SNPs (rs1613662,rs1654419) sign. morefrequent in SPS group; 2 SNPs(rs1671153, rs1654419)significantly more frequent inType II compared with controls

Sokol et al41 27 patients with SPS (fetal loss: 27, W;7, TI/20, TII); 42 controls; whites

3 SNPs significantly morefrequent (rs1671153,rs1654419, rs1613662) in SPSgroup; sign. Higher occurrenceof 2 haplotypes (CTGAG,CGATAG)

Kubisz et al40 71 patients with SPS (stroke; 24 M/47 W; 17 TI/52 TII/2, TIII);77 controls; whites

No significant differencesbetween SPS and controlgroup; SNP rs12610286,haplotype TTGTGA sign. morefrequent in SPS Type I com-pared with controls

Kubisz et al(Peter Kubisz, MD, DSc,Unpublished data,March 2013)

23 patients with SPS (fetal loss 23, W;23, TII); 42 controls; whites

4 Gas6 SNPs (rs7400002,rs1803628, rs8191974,rs9550270), 2 PEAR1 SNPs(rs12041331,rs12566888).2 MRVI1 SNPs (rs7940646,rs187445)

1 GAS6 SNP (rs7400002) and 1PEAR1 SNP (rs, rs12566888)significantly more frequent inSPS group

Abbreviations: GP, glycoprotein; M, men; sign, significant; SNP, single nucleotide polymorphism; SPS, sticky platelet syndrome; T, type; VTE, venous

thromboembolism; W, women.

Table 5 Specific clinical features of SPS

• Young adults (< 40 years), usually without known riskfactors.

• Pregnant woman often affected; pregnant women oftenaffected; association with fetal loss syndrome

• Often atypical/less common localization of thrombosis(retinal veins, cerebral sinuses)

• Both arterial (more often) and venous thrombosispresented

• Recurrent/new thrombosis during adequateanticoagulation therapy (especially VKA)

• Often positive family history for TE with both gendersaffected

Abbreviations: TE, thromboembolism; VKA, vitamin K antagonists.



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Thrombosis is localizedmostly in typical sites—the deepveins

in case of venous TE and coronary and cerebral arteries in case

of arterial TE. However, less common sites (e.g., cerebral

sinuses, retinal, and placental vessels) are also often affected.

SPS seems to be a leading underlying defect in these events. It

was found in 50.0% of patients with retinal vascular throm-

bosis and in 16.2% with fetal wastage syndrome.11

The first 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. In women, it often occurs

during pregnancy and is associated with complications

related to impaired placental vascularization, such as in-

trauterine growth retardation or fetal loss. In our cohort,

fetal loss or other pregnancy complications were some of

the main clinical manifestations of the syndrome—they

were found in 18.7% of all women with SPS. As shown by

Bick and Hoppensteadt in their analysis of 351 womenwith

recurrent miscarriage, SPS was presented in a substantial

number (18.2%) of these cases.21 With these results in

mind, it seems rational to recommend testing for SPS in

the differential diagnosis of women with fetal loss or other

pregnancy complications.

The recurrence of thrombosis during adequate anticoagu-

lation therapy with low-molecular-weight-heparin (LMWH)

or vitamin K antagonists (VKA) is an interesting clinical

feature, reported by several authors.14,23,27,28 The patient

with initial venous thrombosis or pulmonary embolism (PE),

under efficient anticoagulation treatment (e.g., therapeutic

prolongation of prothrombin time in case of VKA) and

suffering from the arterial or new venous thrombosis in a

short time (few months) after the first event, represents a

typical scenario. The inability of conventional anticoagulation

drugs to directly inhibit platelet functions is regarded as a

cause.

In initial reports, SPS was seen as an isolated defect of

hemostasis. With the growth of the number of diagnosed

patients, combinations with other inherited (predominantly

activated protein C resistance [APC-R] caused by the FV Leiden

mutation, and FII20210A) or acquired (predominantly elevat-

ed FVIII and antiphospholipid syndrome) thrombophilic dis-

orders were reported.15,20 According to the study by

Andersen, approximately one-third of patients with SPS

have a combined thrombophilic defect.15 Ruiz-Argüelles

and associates showed similar findings in larger proportion

of patients—in 17 (77.3%) of 22 patients with SPS.20 Even

though the number of patients included in the above-men-

tioned studies was small, the concomitant presence of SPS

with other disorders underlines the importance of complex

thrombophilia testing. The patients with combined defects

are at higher risk of recurrent thrombosis and usually require

different therapeutic approach.

SPS is thought to be an inherited disorder and a positive

family history of TE is found in a substantial number of

patients. However, the family history may be negative in

approximately one–third of patients. Several family studies of

patients with SPS (and our own experience as well) showed

that some of their relatives fulfilled laboratory criteria for SPS

but remained clinically asymptomatic throughout their life

up to higher age. It seems, that other factors, especially

acquired risk factors for thrombosis, albeit weak and clinically

irrelevant alone (e.g., oral contraceptives, pregnancy, and

stressful events with increased secretion of EPI), may be

crucial for the clinical manifestation of the syndrome. The

relation between the appearance of thrombotic event and

stressful situation in SPS, noted by several authors, supports

this idea.10,14

Therapy of Sticky Platelet Syndrome

Studies have shown that antiplatelet drugs are efficient in

both treatment and prophylaxis of TE in SPS, whereas other

antithrombotics, although successfully used in other com-

mon thrombophilic disorders (APC-R and FII20210A), can-

not avoid the thrombosis recurrence.10,14 Despite the

variety of antiplatelet drugs available, ASA remains the

treatment of choice.10,11,14 In most treated patients, low

doses (80–100 mg/d) were efficient enough and led to the

normalization of aggregation pattern. In patients who did

not achieve adequate response to the initial low ASA,

escalation of the dose up to 325 mg/d 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 tried (►Fig. 2).10

The treatment of patients with SPS combined with other

thrombophilic disorder(s) is problematic and, according to

the concomitant defect, requires combination of antith-

rombotics—usually VKA or LMWH with antiplatelet drugs.

There are no universal recommendations, and treatment

should be individualized; however, treatment is often

rather accompanied by complications related to the ad-

verse events of medication (especially bleeding) or throm-

bosis recurrence.16,30

Fig. 2 Treatment algorithm of SPS. ADP, adenosine diphosphate; ASA,

acetylsalicylic acid; SPS, sticky platelet syndrome.



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Conclusion

Despite several unresolved issues and likely infrequent prev-

alence in the general population, SPS seems to be a disorder

relevant for clinical practice. With its affection of predomi-

nantly young adults, relation to fertility issues, familial oc-

currence, distinct laboratory diagnostics, and treatment, its

inclusion in screening of TE seems to be beneficial, at least in

selected cases (women of child-bearing age and patients

younger than 40 years). However, more clinical data will be

useful for further understanding of the syndrome, especially

its genetics.

Acknowledgments

The authors declare no conflicts of interest regarding this

article. Institutional funds and funds from projects CEPV II

(ITMS 26220120036) and CEVYPET (ITMS 26220120053)

were used to carry out the work.

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Sticky Platelet Syndrome

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