526
Sticky Platelet Syndrome: History and Future Perspectives
1 Department of Haematology and Transfusion Medicine, National
Center of Haemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin of the Comenius University in Bratislava, University Hospital in Martin, Martin, Slovakia 2 Centro de Hematología y Medicina Interna, Clínica Ruiz, Puebla, México 3 School of Medicine, Universidad de las Américas, Puebla, México 4 School of Medicine, Universidad Popular Autónoma del Estado de Puebla, Puebla, México
Jan Stasko, MD, PhD1
Address for correspondence Peter Kubisz, MD, DSc, National Center of Haemostasis and Thrombosis, Department of Haematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin of the Comenius University in Bratislava, University Hospital in Martin, Kollarova 2, Martin 036 59, Slovakia (e-mail: [email protected]); or Guillermo J. Ruiz-Argüelles, MD, FRCP (Glasg), MACP, Centro de Hematología y Medicina Interna, Clínica Ruiz, 8B Sur 3710, 72530 Puebla, Pue., México (e-mail: [email protected]).
Semin Thromb Hemost 2014;40:526–534.
Abstract
Keywords
► sticky platelet syndrome ► platelet hyperaggregability ► thrombophilia ► platelet disorders ► acetylsalicylic acid
The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait, characterized by increased in vitro platelet aggregation after low concentrations of adenosine diphosphate and/or epinephrine. Its clinical manifestation includes arterial thrombosis, pregnancy complications (fetal growth retardation and fetal loss), and less often venous thromboembolism. SPS was considered to be a rare thrombophilic disorder, but it can be found relatively often as a cause of unexplained thrombosis, particularly among patients with arterial thrombosis such as stroke. The syndrome was recognized as a distinct disorder in 1983 by Holiday and further characterized in the 1980s and 1990s, with Mammen and Bick providing the key findings. Although recognized for more than 30 years, significant issues, namely the syndrome’s etiology, inheritance, and epidemiology, remain unclear. The aim of the first part of this review is to summarize the previous 35 years of the research into, and to provide a brief historical account of, SPS. The history section is focused particularly on the work of two most prominent investigators: Eberhard F. Mammen and Rodger L. Bick. The second part summarizes the present understanding of the syndrome and outlines unresolved issues and the trends in which the future research is likely to continue.
Sticky platelet syndrome (SPS), a prothrombotic platelet disorder characterized by increased in vitro platelet aggregation after activation with low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI), is, together with other inherited qualitative platelet disorders,1 regarded as a rare disease with a rather limited clinical evaluation per-
formed to date. Furthermore, the research of thrombotic qualitative platelet disorders such as SPS, in contrast to the hemorrhagic ones, has become more intense just in the past 35 years. However, since thromboembolism (TE), both arterial and venous, is nowadays regarded as an important cause of mortality, morbidity, and health insurance spending in the developed world, the understanding of these defects has become essential.2,3
Dedicated to the early pioneers in SPS, particularly to Drs. Eberhard F. Mammen (1930–2008) and Rodger L. Bick (1943–2008).
published online June 9, 2014
Issue Theme A Short History of Thrombosis and Hemostasis: Part I (40th Year Celebratory Issue); Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).
Copyright © 2014 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-0034-1381235. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Peter Kubisz, MD, DSc1 Guillermo J. Ruiz-Argüelles, MD, FRCP (Glasg), MACP2,3,4 Pavol Holly, MD, PhD1 Guillermo J. Ruiz-Delgado, MD2,3
SPS is thought, according to the present data and at least by a few investigators, to be the most common inherited prothrombotic platelet defect and thus likely to be of the greatest clinical importance. The primary aim of this review is to summarize the past 35 years of the research into SPS and thus provide a brief historical account of SPS with emphasis given on the most relevant studies. Second, we aim to point out the unresolved issues and outline the trends in which the future research is likely to continue.
Historical Overview of Sticky Platelet Syndrome From the Discovery of Platelets to Discovery of Related Qualitative Disorders Platelets as separate components of blood were recognized in the late 19th century in the pioneering studies of Bizzozero4 and Osler,5 their first description dating back to 1873. It is of interest that both authors gave not only the morphological description of platelets but correctly recognized their involvement in blood clotting. Furthermore, in his pathological studies from the 1880s, Osler provided evidence for the participation of platelets in human thrombotic disease, as he identified these small cells in white thrombi formed on atherosclerotic plaques, in vegetations on heart valves, and in aortic aneurysms.6 The role of platelets in hemostasis was further proved by several clinical studies, such as the ones published by Hayem in 19007 and Duke in 1910.8 Through the observation of patients with thrombocytopenia, Hayem and Duke showed that platelet count was inversely related to bleeding in humans and its rapid cessation could be achieved with the increase in platelet count by the means of blood transfusion. Although quantitative changes—namely thrombocytopenia of various causes—were identified in the 1880s as the first hemostatic defects related to platelets,9,10 the description of the first qualitative disorder followed relatively soon, only a few years, later—being May–Hegglin anomaly—as described by May in 1909.11 The first quantitative defects to be described were—unsurprisingly—those characterized by unique morphological features of platelets (May–Hegglin anomaly, Bernard–Soulier syndrome) or disturbances in coagulation tests established in that time (e.g., clot retraction— Glanzmann thrombasthenia).10 The deeper insight in the platelet morphology and physiology were provided by the works of Bernard, Caen, Roskam, Soulier, and others, together with the development of specialized laboratory methods— glass bead platelet retention assay by Hellem and its modifications, turbidimetric platelet aggregometry by Born and O’Brien, and new analytic methods in biochemistry. These all took place from the 1920s to the 1960s, and were crucial for the better understanding of the processes involved in primary hemostasis and platelet activation, as well as for the description of other platelet defects.9,10 Among the tests introduced, the turbidimetric platelet aggregometry developed independently by Born12 and O’Brien13 in 1962 became of great use. This principally simple and reproducible technique, based on
Kubisz et al.
the continuous recording of the transmission of light through a cuvette containing stirred platelets at a constant temperature, allowed for the characterization of the platelet effects of the different agonists, including ADP and EPI. It revealed specific patterns of aggregation after addition of different agonists and enabled the differential diagnosis and further characterization of several qualitative platelet disorders. As mentioned earlier, qualitative platelet disorders were identified relatively soon after the initial descriptions of platelet function—in the early 20th century. Although the role of platelets in both thrombotic and bleeding disorders was recognized almost immediately after their morphological description, the clinical research in this field was rather one-sided, focused predominantly on disorders manifested with increased bleeding. From the beginning of the 20th century, great effort, research time, and foundations were invested into the characterization of hemorrhagic disorders, whereas prothrombotic ones were recognized much later and, in fact, never really “hit the spotlight.” Whereas, Glanzmann thrombasthenia and Bernard–Soulier syndrome, two most widely known qualitative bleeding platelet disorders, were initially described in 191814 and 1948,15 respectively, and were preceded or followed by the identification of a few other bleeding thrombocytopathies,9,10 the publication of the first work dedicated to the prothrombotic qualitative platelet disorder—the one that would later become known as SPS— dated back to only 1979 (►Fig. 1).16
The Discovery of SPS: From Its Initial Description to Full Clinical Picture and Diagnostic Criteria In 1979, al-Mefty et al described 22 patients with transient ischemic attack (TIA), all of whom showed on repeated testing an increased platelet adhesion and/or aggregation.16 No other hemostatic disorder (known at that time), as well as no common cause of central nervous system ischemia (e.g., atherosclerotic cerebral vascular disease, cardiac source of emboli, migraine, arteritis, or collagen disease) were identified in any of the subjects. al-Mefty suggested that the platelet hyperaggregability could be the underlining cause of TIA in those individuals. The idea was supported by his observation that the administration of an antiplatelet agent—acetylsalicylic acid (ASA) led to the rapid cessation of the symptoms, whereas its discontinuation led in some cases to their recurrence. He concluded that there was a specific group of patients with TIA in whom the abnormality of platelet function was a sole cause of the event. In 1983, Holiday et al presented a similar clinical observation at the 9th International Joint Conference on Stroke and Cerebral Circulation in Arizona in a group of patients with ischemic stroke or TIA and platelet hyperaggregability after low concentrations of EPI and/or ADP.17 Holiday postulated this condition as a distinct clinical syndrome and suggested the term SPS to emphasize the underlining defect of platelet aggregation. However, several issues, particularly etiology and epidemiological data, remained unclear at that time. Surprisingly, the earlier mentioned reports did not lead to the expected great interest in platelet hyperaggregability. In the next 20 years, a rather limited number of Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
527
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
Fig. 1 Timeline of important events related to SPS. ADP, adenosine diphosphate; ASA, acetylsalicylic acid (aspirin); EPI, epinephrine; PLT, platelet; SNP, single nucleotide polymorphism; SPS, sticky platelet syndrome; TE, thromboembolism; TIA, transient ischemic attack; VKA, vitamin K antagonists.
investigators published case reports or small retrospective series of patients with platelet hyperaggregability to ADP and/or EPI, no other hemostatic defect, and thrombotic events.18–28 SPS has been found in individuals who suffer not only central nervous system ischemia18–21 but also a broad spectrum of thrombotic events; both arterial and venous thromboses have been reported, although the arterial events have been observed more frequently.22–28 The thrombotic events associated with SPS include angina pectoris and myocardial infarction (MI),19 thrombosis of retinal vessels,20 fetal loss and growth retardation,28 deep venous thrombosis, and pulmonary embolism.23,24 Most of the studies published in the 1980s and 1990s were limited in the number of patients, retrospective in design, and in general add little to the knowledge of the syndrome past its clinical manifestation. However, the works of two investigators—Mammen and Bick—and their groups—did add important data for further understanding and definition of the syndrome. Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
The observations made by Mammen, one of the original coworkers of Holiday, were particularly important for the more precise definition of SPS. Within a decade after Holiday’s report, Mammen et al collected extended clinical data that enabled him to outline detailed characteristics, classification and diagnostics of the syndrome. In 1984, he treated a young woman who suffered from MI during the third semester of her first pregnancy. An extensive laboratory testing failed to reveal any hemostatic abnormalities except for increased in vitro platelet aggregation after both ADP and EPI. While analyzing the patient’s history, Mammen discovered that her mother and 18-year-old brother suffered from arterial thrombotic events as well—the mother had MI during one of her pregnancies and the brother had unexplained repeated attacks of angina pectoris despite normal coronary arteries on angiography.25 On the basis of this case, Mammen came up with the idea that the syndrome could be found not only in patients with stroke but also in others who suffered from thrombotic events, be inherited in an autosomal pattern
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
528
and behind otherwise unexplained thrombotic events, especially in young individuals without severe risk factors. Interestingly, he noted “stressful situations” as a provoking factor for the thrombosis.25 In the following years, Mammen et al identified numerous patients with proven platelet hyperaggregability by laboratory testing and thromboembolic events—as well as a few other families with several affected members and generations. His experience with tens of cases was summarized in several articles published from the mid1990s to 2003 and enabled him to propose clearly defined laboratory and clinical criteria for the syndrome (►Table 1).21,25,26 These criteria were respected and used as a standard in all other subsequent works on SPS. On the basis of the pattern of platelet aggregation, Mammen identified two types of the syndrome: Type I, characterized by hyperaggregability after both ADP and EPI, and Type II, characterized by hyperaggregability after EPI only, with this being more frequent. The classification, however, was based only on laboratory characteristics and Mammen did not observe any relation of SPS types to clinical manifestation, treatment, or course. As for the treatment, he did observe an excellent efficacy of ASA—even in low doses (range, 80–100 mg/day)—in most of the patients, confirming al-Mefty’s initial findings. The work of Mammen was further expanded and completed by Bick.26–28 He confirmed Mammen’s conclusions on diagnostics and, based on his own observation, added the least frequent Type III—hyperaggregability after ADP only—to the syndrome’s classification.26 In accordance with Mammen, he did not confirm any relation of the laboratory-defined types (Types I, II, or III) to clinical or therapeutic issues. Bick was among the first to note SPS in patients with venous TE (VTE)26; he also confirmed the good efficacy of low-dose ASA and recommended it as the firstchoice treatment. His further work focused on two problems —on the role of the syndrome in the subpopulations of patients with unexplained thromboembolic events (e.g., unprovoked thrombosis) and women with child-bearing issues.
Kubisz et al.
He showed that SPS was frequent in both the groups. In the study of 153 patients with unexplained thromboembolic events, he found SPS in 17.6%.26 In collaboration with Hoppensteadt, he showed that a significant number of women with recurrent miscarriage—18.2% of 351 tested individuals in his cohort—fulfilled the criteria of SPS.28 He thus provided a strong clinical evidence for the relation of SPS to fetal loss.28 On the basis of his analyses of the largest patient cohorts to date, he concluded that SPS was likely to be, at least in the populations with unexplained thrombotic events and of white origin (the origin of his groups), one of the most frequent thrombophilias, second only to the resistance to activated protein C (APC-R), and advocated for its wider testing.26,27 Besides these two leading investigators, some interesting features of the syndrome were noted by other researchers as well. In 1998, Chittoor et al reported a case of a 30-year-old woman, who initially suffered from the thrombosis of the superior sagittal sinus manifested as sudden disturbances of sight.24 Anticoagulation with warfarin was initiated and despite being properly managed with the international normalized ratio kept in the therapeutic range, the patient suffered from recurrent deep venous thrombosis of the lower extremities 7 and 10 months later, while still on anticoagulant treatment. The defect of platelet aggregation was identified only after the three earlier mentioned thrombotic events. Warfarin was discontinued and alternate treatment with ASA was initiated. During the 2 subsequent years, while on ASA, the patient had no new episode of TE. The ineffectiveness of anticoagulation and the alternate surprisingly effective treatment and prophylaxis with antiplatelet drugs have since also been observed by others.29–31 The inability of standard anticoagulants to directly influence platelet aggregation is believed to be the most plausible explanation of this phenomenon. In 1999, Chaturvedi and Dzieczkowski were first to describe the occurrence of SPS together with other inherited thrombophilic disorder in the same individual.32 Whereas all
Table 1 Diagnostic criteria for SPS according to Mammen25,26 Platelet aggregation after activation with ADP a
EPI
Concentration of reagent (µM)
0.58
1.17
2.34
0.55
1.1
11.0
Normal rangeb (% aggregation)
0–12
2–36
7.5–55
9–20
15–27
39–80
Diagnostic criteria Suggestive diagnosis:
• History of TE and hyperaggregability to only 1 conc. of 1 reagent
Firm diagnosis:
• History of TE and hyperaggregability to 2 conc. of 1 reagent • History of TE and hyperaggregability to 1 conc. of both reagents • History of TE and hyperaggregability to only 1 conc. of 1 reagent, repeatedly tested
Abbreviations: ADP, adenosine diphosphate; EPI, epinephrine; TE, thromboembolism. Adapted from Mammen.25,26 a The given concentrations were proposed by Mammen for light transmission aggregometry and were used in the majority of to-date published works. b Only informative (based on the authors’ own experience) should be determined within each laboratory. Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
529
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
previous reports found SPS in patients without any other hemostatic disturbances, they described a case of a young woman with recurrent stroke and combined thrombophilia— protein S deficiency, APC-R caused by FV Leiden heterozygosity and SPS. The concomitant occurrence of SPS with other well-defined thrombophilias (elevated factor VIII, antiphospholipid syndrome, prothrombin G20201A, and hyperhomocysteinemia) were subsequently reported.29,33–37 In fact, as shown by Ruiz-Argüelles et al, most patients with SPS phenotype might display other thrombophilic conditions, both inherited and acquired. Thus, the coexistence of SPS with other conditions may be required in some cases for the development of vaso-occlusive episodes and clinical manifestation, in accordance with the concept of multifactorial thrombophilia.37
The Past 10 Years of SPS Research: What Has It Been Able to Add? In general, the research of SPS in the first years of the new millennium could be divided into two main directions. One group of investigators focused on providing further data on the clinical presentation and treatment, whereas the second group took greater interest into the pathophysiology of the syndrome. In the past decade, more case reports and case series, providing an ever increasing evidence on the clinical picture,29–35,37–49 treatment50 or familial occurrence and autosomal trait of inheritance,36,51 were published. The presented clinical data provided further support for the previous observations but add no new characteristics or treatment strategies with the exception of the manuscripts written by El-Amm et al,34 Mühlfeld et al,40 Yagmur et al,45 Lewerenz et al,33 Moncada et al,49 and Velázquez-Sánchezde-Cima et al.50 El-Amm et al, Mühlfeld et al, and Yagmur et al described platelet hyperaggregability in a new clinical setting—in the patients undergoing hemodialysis or renal transplant recipients with thrombotic complications or impaired function of the graft. The results of Yagmur et al are particularly worth mentioning. They evaluated platelet aggregation after EPI in 30 hemodialysis patients and 34 renal transplant recipients and found a surprisingly high prevalence of SPS phenotype— in 67 and 82%, respectively—in those with subsequent thromboembolic events. The authors suggested that the testing of platelet hyperaggregability may supplement the assessment of thromboembolic complications in patients with chronic kidney disease.45 Lewerenz et al and Moncada et al reported cutaneous changes—atrophy blanche, livedo reticularis, erythema nodosum, Raynaud phenomenon, and livedoid vasculopathy—in individuals with the SPS phenotype.33,49 As for the treatment, most of the physicians have been following the example of Mammen and Bick and using ASA as the drug of choice. The report from Velázquez-Sánchez-deCima et al on their experience with ASA, clopidogrel or the concomitant use of both agents in 55 patients with SPS is thus innovative and is the first prospective study of the treatment in SPS.50 They observed an excellent efficacy of both ASA and Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
the combination therapy with ASA and clopidogrel in the prevention of rethrombosis. Their results provided broader clinical data on clopidogrel and showed that the drug might be of use in this setting. So far, most of the data on SPS therapy were taken from the patients who received ASA only; the use of other antiplatelet agents was scarce and limited to few individual case reports.23,40,44 From the initial descriptions, the familial occurrence of SPS was noted. Thus, the syndrome has been regarded, at least in a significant proportion of affected individuals, as a hereditary disorder. Despite the clear clinical definition and strong evidence of familial occurrence, the exact genetic cause of SPS has remained unidentified. Mammen suggested that the defects of membrane platelet glycoproteins (GP) involved in their activation and subsequent actions were likely behind the syndrome.22 However, he was unable to identify any specific genetic changes. Kubisz et al were able to show that the pathophysiology of SPS was indeed related to platelet activation processes. They found the increased surface expression of CD62 and CD51—neoantigens expressed only after platelet activation—in SPS patients in the “calm” state (e.g., outside of acute thromboembolic event) in comparison to normal population.52 In the late 1990s and the 2000s, the results of several genetic analyses suggested the link between the certain single nucleotide polymorphisms (SNPs) of platelet GP and platelet hyperaggregability (increased aggregation after EPI in the carries of allele A2 of GpIIIa PLA A1/A2),53 risk of thrombotic events such as cardiovascular disease, MI, or stroke (increased risk in the carriers of certain SNPs of GpVI or allele A2 of GpIIIa PLA A1/A2, decreased risk in the carries of allele A of SNP Gas6 c. 834 þ 7G > A)54–57 or regulation of platelet response to physiological agonists (GP6 locus).58 The identification of genetic changes of GpIIIa, Gas6 protein, and GpVI as factors influencing platelet aggregation made their genes promising targets in the search for the cause of SPS. In the last years, two investigators—Ruiz-Argüelles et al and Kubisz et al—and their groups became interested in this particular field. However, the results they published so far failed to identify a single genetic defect responsible for SPS or to show a consistent relation of genetic changes in GpIIIa, Gas6 protein, and GP6 genes to SPS or its types.59–64 Thus, the genetic background has yet to be revealed.
Present Understanding of SPS: Where We Currently Stand On the basis of the earlier discussed to-date published studies, the present understanding of SPS can be summarized as follows. SPS is defined by its clinical and laboratory characteristics, with the criteria originally established by Mammen still in use (►Table 1). SPS is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait (although its presence among relatives is not a condition for making the diagnosis and is not seen in all patients), characterized by increased in vitro platelet aggregation after low concentrations of ADP and/or EPI. The syndrome is associated with arterial thrombosis, pregnancy complications such as fetal growth retardation and
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
530
loss, and VTE, though the latter is less frequent. Furthermore, SPS might be associated with an impaired graft function in renal transplantation. The clinical presentation of SPS can have several distinct features. The first thrombotic event usually occurs in patients younger than 40 years and with or without acquired risk factors, such as pregnancy, puerperium, or exogenous estrogen use. Once the syndrome shows family occurrence, both genders are affected. Commonly used anticoagulants such as vitamin K antagonists are usually inefficient in the treatment and prophylaxis of thromboembolic events and their use may result in the recurrence of thrombosis. Antiplatelet agents, particularly ASA, are very effective both in treatment and prevention of thrombosis; even low-dose ASA (range, 80–100 mg/day) leads in the majority of patients to the normalization of hyperaggregability on repeated testing.50 The experience with other antiplatelet agents is limited, although recent clinical evidence supports the use of clopidogrel.50 The few patients with SPS that display aspirin refractoriness can be effectively treated with clopidogrel; accordingly, it may be advisable to retest for platelet hyperaggregability after antiplatelet drugs have been started. SPS can occur in a considerable number of patients displaying other thrombophilic conditions, so the screening of other common thrombophilias should not be neglected. According to aggregation pattern, three types of the syndrome can be identified, although this subclassification has no known clinical or therapeutic consequences. Despite several studies focused on SNPs of several platelet GPs (GpIIIa, Gas6 protein, or GpVI), the exact genetic defect responsible for the syndrome remains unknown.
Open Issues and Future Perspectives Although the clinical presentation and laboratory findings in SPS have been described in detail, several issues remain unresolved, most prominently in pathophysiology, epidemiology, and treatment of the syndrome.
Pathophysiology SPS is usually referred to as an inherited platelet disorder. As shown by several authors, the familial occurrence of the syndrome is not uncommon, with an autosomal trait of inheritance and infliction of both women and men. However, there are several unclear issues, once one tries to describe the inheritance pattern in greater detail. First, as the underlining genetic defect is not known, it is impossible to decide whether the pattern is dominant or recessive. Second, in several published family pedigrees, the same type of the syndrome may not be present in all members and generations within the affected family.51 Third, additional affected relatives or descendants were not identified for all patients diagnosed with SPS and on occasion the family history might be completely negative. The discrepancies in inheritance pattern, together with the failure of the genetic studies to identify a single underlining genetic defect and laboratory heterogeneity of the syndrome with three clearly distinct types might suggest, in our opinion, two explanations. First, SPS might have a multifactorial
Kubisz et al.
genetics—various mutations of the same or even various genes resulting in similar phenotypes. Second, because the diagnosis of SPS is made solely on the clinical (thromboembolic event) and laboratory criteria (platelet hyperaggregability) and not on genetic testing, individuals with both inherited and acquired changes of platelet aggregation may be included in the currently diagnosed patient groups. There is growing evidence, for example, that the same laboratory phenotype as in inherited SPS could be seen in certain metabolic (diabetes mellitus and atherosclerosis) or inflammatory (sepsis and systemic immune disorders) diseases.65,66 In this context, a recent publication from Yagmur et al, identifying a surprisingly high number of individuals with platelet hyperaggregability with EPI among patients with chronic renal disease undergoing hemodialysis or renal transplantation, is very interesting.45 In our opinion, this scenario might be representative of the “acquired” SPS phenotype. It is therefore likely that the previous studies have included individuals with both the “inherited” and “acquired” forms of platelet hyperaggregability, as their distinction was not, to our knowledge, rigorously addressed therein. The separation of these two entities and the initiation of new clinical studies with precisely chosen participants will be crucial for the better understanding of the syndrome and elucidation of the conflicting genetic results. It is also critical to standardize the methods used to assess the SPS phenotype. ►Table 1 shows the diagnostic criteria proposed by Mammen et al20,25 as well as the laboratory studies needed to define the condition. Ideally, all laboratories should employ comparative concentrations of aggregating agents to conduct the tests and to assess the patterns representative of normal individuals and abnormal aggregation to a lower concentration of agonist; this will improve comparability of results between laboratories.
Epidemiology Although a decent number of scientific reports on SPS have been published to date, the epidemiological data are surprisingly limited. The limitation might have been caused, at least partially, by the lack of recognition of the disorder and scepticism shared by a significant proportion of clinicians, as discussed later. The exact prevalence of the syndrome in the whole population as well as in subpopulations with thrombotic events or even among patients with a distinct localization of thrombosis (e.g., stroke) is not known. Most of the reports were individual case reports or small case series in design and thus limited in number of patients. In those cases when a larger cohort was evaluated, only selected proportion of patients with TE—almost exclusively with unexplained events—were involved. The criteria used for the selection of participants were not clearly stated in most of the works. Second, almost all to-date studies analyzed the individuals of white origin; the data on other human races are therefore limited. Even the little data available so far show striking racial differences. For example, the distribution of SPS subtypes may be different in distinct populations and does not seem to be related to the severity of the disease nor to its Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
531
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
clinical presentation. Type II is the most frequent variant of SPS in white populations, whereas Type I is the most frequent variant in Mexican mestizos.36,37,49,58,67 In Mexican mestizos, the SPS phenotype is the second most frequent inherited cause of thrombophilia.68 The knowledge of the epidemiological data which have to be delivered by new studies might be helpful in decisions on several issues: whether the testing of SPS should be included in the standard thrombophilia screening, whether the patients with certain localization of thrombosis should be tested in advance, or whether the testing of the extended family of the affected individuals is likely to identify a reasonable number of new cases and be economically justified. At present, most of these questions have to be answered by the treating physician individually, on a case-to-case basis.
Treatment It has been repeatedly shown by various authors that antiplatelet agents, especially ASA, are efficient both in treatment and prevention of thrombosis in SPS. However, several therapeutic problems, some rather similar to other thrombophilic disorders, were not fully covered in the published studies. First, the data on the antiplatelet agents other than ASA, and in relation to dosing and efficacy, are limited. It has been assumed that they should be equally effective as ASA in the doses used in other conditions that required platelet inhibition, but the clinical evidence is scarce (in the case of clopidogrel) or missing (in the case of other agents). The laboratory evaluation and monitoring of the antiplatelet treatment should also be assessed. Second, as in other thrombophilias, the duration of the antiplatelet treatment, the treatment of asymptomatic individuals including children, screening of asymptomatic relatives, and the prophylaxis in risk situation such as pregnancy or invasive procedures are among the controversial questions commonly faced by physicians in routine practice but with little or no clinical evidence in terms of reasonably large retrospective studies or randomized trials. Third, there are no universal recommendations for the treatment of patients with SPS and concomitant thrombophilic disorder(s). The presence of the other hemostatic defect(s) usually leads to the administration of the combination of antithrombotics (antiplatelet agents with anticoagulants such as vitamin K antagonists) with individualized dosing. However, none of the published studies have focused on this specific subgroup and thus the clinical evidence that will justify this practice is lacking. These fundamental therapeutic issues were not intentionally addressed in previous works. Their answering, however, is essential for the rationale and adequate therapeutic management and represents, undoubtedly, the challenge for future clinical trials.
Scepticism Regarding Sticky Platelet Syndrome The recognition of SPS as a true entity has prompted the development of both promoters and opponents to the Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
concept. Up to now, the lack of a definite molecular basis for the condition has been a major obstacle for its acceptance as a distinct entity and several sceptical scientists are still reluctant to consider this disease as a true distinct clinicopathological entity. Some experts still consider the aberrant platelet aggregation responses seen in this condition as laboratory artifacts.
Conclusion We sincerely hope that this article will result in the development of additional interest in other investigators who could eventually contribute to the better understanding and acceptance of the syndrome, its pathophysiology and treatment, with the goal of helping patients afflicted by thrombophilia, currently one of the leading causes of death in developed societies.
Acknowledgments The work was supported by the project APVV 00–222–11, Vega 1/0016/12, and Martin Center of Biomedicine (Biomed Martin), ITMS: 26220220187.
Declaration of Conflicting Interests The authors state that they have no conflict of interest to declare with respect to the research, authorship, and publication of this article.
References 1 Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders.
Haemophilia 2012;18(Suppl 4):154–160 2 Cohen AT, Agnelli G, Anderson FA, et al; VTE Impact Assessment
3 4
5 6 7 8 9 10 11 12 13 14
Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98(4):756–764 Ingall T. Stroke—incidence, mortality, morbidity and risk. J Insur Med 2004;36(2):143–152 Bizzozero J. Über einen neuen Formbestandteil des Blutes und dessen Rolle bei der Thrombose und der Blutgerinnung. Virchow’s. Arch Pathol Anat Physiol Klin Med 1882;90:261–332 Osler W. An account of certain organisms occurring in the liquor sanguinis. Proc R Soc Lond 1874;22:391–398 Osler W. On certain problems in the physiology of the blood corpuscles. The Medical News 1886;48:421–425 Hayem G. Leçons sur les maladies du sang. Paris: Masson; 1900 Brinkhous KMWW. W. W. Duke and his bleeding time test. A commentary on platelet function. JAMA 1983;250(9):1210–1214 de Gaetano G. Historical overview of the role of platelets in hemostasis and thrombosis. Haematologica 2001;86(4):349–356 Coller BS. Historical perspective and future directions in platelet research. J Thromb Haemost 2011;9(Suppl 1):374–395 May R. Leokozyteneinschlusse. Deutsch Arch Klin Med 1909; 96:1–6 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–929 O’Brien J. Platelet aggregation: Part II Some results from a new method of study. J Clin Pathol 1962;15(5):452–455 Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis 2006;1:10
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
532
Kubisz et al.
15 Bernard J. History of congenital hemorrhagic thrombocytopathic
37 Ruiz-Argüelles GJ, López-Martínez B, Valdés-Tapia P, Gómez-Ran-
dystrophy. Blood Cells 1983;9(2):179–193 al-Mefty O, Marano G, Raiaraman S, Nugent GR, Rodman N. Transient ischemic attacks due to increased platelet aggregation and adhesiveness. Ultrastructural and functional correlation. J Neurosurg 1979;50(4):449–453 Holiday PL, Mammen E, Gilroy J. Sticky platelet syndrome and cerebral infarction in young adults. Paper presented at: The Ninth International Joint Conference on Stroke and Cerebral Circulation; 1983; Phoenix, AZ Warrier I, Nigro M, Hillman C, et al. Platelet activation associated with stroke migraine in children. Thromb Haemost 1991;65:772 Berg-Dammer E, Henkes H, Trobisch H, Kühne D. Sticky platelet syndrome: a cause of neurovascular thrombosis and thromboembolism. Interv Neuroradiol 1997;3(2):145–154 Mammen EF, Barnhart MI, Selik NR, Gilroy J, Klepach GL. “Sticky platelet syndrome”: a congenital platelet abnormality predisposing to thrombosis? Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115(3):361–365 Frenkel EP, Mammen EF. Sticky platelet syndrome and thrombocythemia. Hematol Oncol Clin North Am 2003;17(1):63–83 Rubenfire M, Blevins RD, Barnhart M, Housholder S, Selik N, Mammen EF. Platelet hyperaggregability in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 1986;57(8):657–660 Bick RL. Sticky platelet syndrome: A common cause of unexplained arterial and venous thrombosis. Clin Appl Thromb Hemost 1998; 4:77–81 Chittoor Elsehety AE, Roberts GF, Laughlin WR. Sticky platelet syndrome: a case report and review of the literature. Clin Appl Thromb Hemost 1998;4:280–284 Mammen EF. Ten years’ experience with the “Sticky platelet syndrome”. Clin Appl Thromb Hemost 1995;1:66–72 Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost 1999;25(4):361–365 Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am 2003;17(1):9–36 Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost 2005;11(1):1–13 Fodor M, Facskó A, Berényi E, Sziklai I, Berta A, Pfliegler G. Transient visual loss triggered by scuba diving in a patient with a petrous epidermoid and combined thrombotic risk factors. Pathophysiol Haemost Thromb 2007;36(6):311–314 Kannan S. Recurrent arterial thrombosis in a young male: sticky platelet syndrome. Internet J Hematol 2008;4(1):4 Sand M, Mann B, Bechara FG, Sand D. Sticky platelet syndrome type II presenting with arterial microemboli in the fingers. Thromb Res 2009;124(2):244 Chaturvedi S, Dzieczkowski JS. Protein S deficiency, activated protein C resistance and sticky platelet syndrome in a young woman with bilateral strokes. Cerebrovasc Dis 1999; 9(2):127–130 Lewerenz V, Burchardt T, Büchau A, Ruzicka T, Megahed M. Livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome [in German]. Hautarzt 2004; 55(4):379–381 El-Amm JM, Andersen J, Gruber SA. Sticky platelet syndrome: a manageable risk factor for posttransplant thromboembolic events. Am J Transplant 2008;8(2):465 Bojalian MO, Akingba AG, Andersen JC, et al. Sticky platelet syndrome: an unusual presentation of arterial ischemia. Ann Vasc Surg 2010;24(5):e1–e6 Ruiz-Argüelles GJ, Alarcón-Urdaneta C, Calderón-García J, RuizDelgado GJ. Primary thrombophilia in México VIII: Description of five kindreds of familial sticky platelet syndrome phenotype. Rev Hematol Mex 2011;12(2):73–78
gel JD, Reyes-Núñez V, Garcés-Eisele J. Primary thrombophilia in Mexico. V. A comprehensive prospective study indicates that most cases are multifactorial. Am J Hematol 2005;78(1):21–26 Kahles H, Trobisch H, Kehren H. Disseminated coronary occlusions and massive pulmonary embolism in a 40-year-old woman [in German]. Dtsch Med Wochenschr 2006;131(13):672–675 Randhawa S, Van Stavern GP. Sticky platelet syndrome and anterior ischaemic optic neuropathy. Clin Experiment Ophthalmol 2007; 35(8):779–781 Mühlfeld AS, Ketteler M, Schwamborn K, et al. Sticky platelet syndrome: an underrecognized cause of graft dysfunction and thromboembolic complications in renal transplant recipients. Am J Transplant 2007;7(7):1865–1868 Mears KA, Van Stavern GP. Bilateral simultaneous anterior ischaemic optic neuropathy associated with Sticky Platelet Syndrome. Br J Ophthalmol 2009;93(7):885–886, 913 Loeffelbein DJ, Baumann CM, Mücke T, Wolff KD, Hölzle F, Kesting MR. Sticky platelet syndrome as a possible cause for free flap failure—a case report. Microsurgery 2010;30(6):466–468 Rac MW, Minns Crawford N, Worley KC. Extensive thrombosis and first-trimester pregnancy loss caused by sticky platelet syndrome. Obstet Gynecol 2011;117(2 Pt 2):501–503 Gehoff A, Kluge JG, Gehoff P, et al. Recurrent strokes under anticoagulation therapy: Sticky platelet syndrome combined with a patent foramen ovale. J Cardiovasc Dis Res 2011;2(1):68–70 Yagmur E, Frank RD, Neulen J, Floege J, Mühlfeld AS. Platelet hyperaggregability is highly prevalent in patients with chronic kidney disease: an underestimated risk indicator of thromboembolic events. Clin Appl Thromb Hemost 2013(e-pub ahead of print) Darulová S, Samoš M, Sokol J, et al. Sticky platelets syndrome in a young patient with massive pulmonary embolism. Am J Case Rep 2013;14:169–172 Tekgündüz E, Demir M, Akyol Erikçi A, Akpınar S, Oztürk E, Kırkızlar O. Sticky platelet syndrome in patients with uninduced venous thrombosis. Turk J Haematol 2013;30(1):48–52 Kubisz P, Stasko J, Holly P. Sticky platelet syndrome. Semin Thromb Hemost 2013;39(6):674–683 Moncada B, Castillo-Martínez C, Ruiz-Argüelles GJ, Valdés-Tapia P, Arenas-Velázquez E. Sticky platelets syndrome: a frequent cause of primary thrombophilia. J Invest Dermatol 2013;133(Suppl 1):S180 Velázquez-Sánchez-de-Cima S, Zamora-Ortiz G, Hernández-Reyes J, et al. Primary thrombophilia in Mexico X: a prospective study of the treatment of the sticky platelet syndrome. Clin Appl Thromb Hemost 2013 (e-pub ahead of print) Šimonová R, Bartosová L, Chudý P, et al. Nine kindreds of familial sticky platelet syndrome phenotype. Clin Appl Thromb Hemost 2013;19(4):395–401 Staško J, Bartošová L, Mýtnik M, Kubisz P. Are the platelets activated in sticky platelet syndrome? Thromb Res 2011;128(1):96–97 Feng D, Lindpaintner K, Larson MG, et al. Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 1999;19(4):1142–1147 Cole VJ, Staton JM, Eikelboom JW, et al. Collagen platelet receptor polymorphisms integrin alpha2beta1 C807T and GPVI Q317L and risk of ischemic stroke. J Thromb Haemost 2003;1(5):963–970 Ollikainen E, Mikkelsson J, Perola M, Penttilä A, Karhunen PJ. Platelet membrane collagen receptor glycoprotein VI polymorphism is associated with coronary thrombosis and fatal myocardial infarction in middle-aged men. Atherosclerosis 2004;176(1):95–99 Muñoz X, Obach V, Hurtado B, de Frutos PG, Chamorro A, Sala N. Association of specific haplotypes of GAS6 gene with stroke. Thromb Haemost 2007;98(2):406–412 Shaffer JR, Kammerer CM, Dorn J, et al. Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians. Nutr Metab Cardiovasc Dis 2011;21(8):546–552
16
17
18 19
20
21 22
23
24
25 26 27
28
29
30 31
32
33
34
35
36
38
39
40
41
42
43
44
45
46
47
48 49
50
51
52 53
54
55
56
57
Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
533
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
58 Johnson AD, Yanek LR, Chen MH, et al. Genome-wide meta-
63 Sokol J, Biringer K, Škereňová M, et al. Platelet aggregation
analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet 2010;42(7):608–613 Kubisz P, Ivankov J, Hollý P, Staško JN, Musiał J. The glycoprotein IIIa PL(A1/A2) polymorphism—a defect responsible for the sticky platelet syndrome? Clin Appl Thromb Hemost 2006; 12(1):117–119 Ruiz-Argüelles GJ, Garcés-Eisele J, Camacho-Alarcón C, et al. Primary thrombophilia in Mexico IX: the glycoprotein IIIa PLA1/ A2 polymorphism is not associated with the sticky platelet syndrome phenotype. Clin Appl Thromb Hemost 2013;19(6):689–692 Kubisz P, Bartosová L, Ivanková J, et al. Is Gas6 protein associated with sticky platelet syndrome? Clin Appl Thromb Hemost 2010; 16(6):701–704 Kubisz P, Ivanková J, Škereňová M, Staško J, Hollý P. The prevalence of the platelet glycoprotein VI polymorphisms in patients with sticky platelet syndrome and ischemic stroke. Hematology 2012; 17(6):355–362
abnormalities in patients with fetal losses: the GP6 gene polymorphism. Fertil Steril 2012;98(5):1170–1174 Kotuličová D, Chudý P, Škereňová M, Ivanková J, Dobrotová M, Kubisz P. Variability of GP6 gene in patients with sticky platelet syndrome and deep venous thrombosis and/or pulmonary embolism. Blood Coagul Fibrinolysis 2012;23(6):543–547 Vieira de Abreu A, Rondina MT, Weyrich AS, Zimmerman GA. Inflammation. In: Michelson AD, ed. Platelets. 3rd ed. Oxford, UK: Elsevier Inc.; 2013:733–766 Ferreiro JL, Gómez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 2010;7(4):251–259 Ruiz-Argüelles GJ, López-Martínez B, Cruz-Cruz D, Esparza-Silva L, Reyes-Aulis MB. Primary thrombophilia in Mexico III: A prospective study of the sticky platelet syndrome. Clin Appl Thromb Hemost 2002;8(3):273–277 Ruiz-Argüelles GJ, Ruiz-Delgado GJ. Trombofilia. In: Ruiz-Argüelles GJ, Ruiz-Delgado GJ, eds. Fundamentos de Hematología. 5th ed. Ciudad de México: Editorial Médicsa Panamericana; 2014:287–296
59
60
61
62
Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
64
65
66 67
68
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
534
Copyright of Seminars in Thrombosis & Hemostasis is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Sticky Platelet Syndrome: History and Future Perspectives
1 Department of Haematology and Transfusion Medicine, National
Center of Haemostasis and Thrombosis, Jessenius Faculty of Medicine in Martin of the Comenius University in Bratislava, University Hospital in Martin, Martin, Slovakia 2 Centro de Hematología y Medicina Interna, Clínica Ruiz, Puebla, México 3 School of Medicine, Universidad de las Américas, Puebla, México 4 School of Medicine, Universidad Popular Autónoma del Estado de Puebla, Puebla, México
Jan Stasko, MD, PhD1
Address for correspondence Peter Kubisz, MD, DSc, National Center of Haemostasis and Thrombosis, Department of Haematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin of the Comenius University in Bratislava, University Hospital in Martin, Kollarova 2, Martin 036 59, Slovakia (e-mail: [email protected]); or Guillermo J. Ruiz-Argüelles, MD, FRCP (Glasg), MACP, Centro de Hematología y Medicina Interna, Clínica Ruiz, 8B Sur 3710, 72530 Puebla, Pue., México (e-mail: [email protected]).
Semin Thromb Hemost 2014;40:526–534.
Abstract
Keywords
► sticky platelet syndrome ► platelet hyperaggregability ► thrombophilia ► platelet disorders ► acetylsalicylic acid
The sticky platelet syndrome (SPS) is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait, characterized by increased in vitro platelet aggregation after low concentrations of adenosine diphosphate and/or epinephrine. Its clinical manifestation includes arterial thrombosis, pregnancy complications (fetal growth retardation and fetal loss), and less often venous thromboembolism. SPS was considered to be a rare thrombophilic disorder, but it can be found relatively often as a cause of unexplained thrombosis, particularly among patients with arterial thrombosis such as stroke. The syndrome was recognized as a distinct disorder in 1983 by Holiday and further characterized in the 1980s and 1990s, with Mammen and Bick providing the key findings. Although recognized for more than 30 years, significant issues, namely the syndrome’s etiology, inheritance, and epidemiology, remain unclear. The aim of the first part of this review is to summarize the previous 35 years of the research into, and to provide a brief historical account of, SPS. The history section is focused particularly on the work of two most prominent investigators: Eberhard F. Mammen and Rodger L. Bick. The second part summarizes the present understanding of the syndrome and outlines unresolved issues and the trends in which the future research is likely to continue.
Sticky platelet syndrome (SPS), a prothrombotic platelet disorder characterized by increased in vitro platelet aggregation after activation with low concentrations of adenosine diphosphate (ADP) and/or epinephrine (EPI), is, together with other inherited qualitative platelet disorders,1 regarded as a rare disease with a rather limited clinical evaluation per-
formed to date. Furthermore, the research of thrombotic qualitative platelet disorders such as SPS, in contrast to the hemorrhagic ones, has become more intense just in the past 35 years. However, since thromboembolism (TE), both arterial and venous, is nowadays regarded as an important cause of mortality, morbidity, and health insurance spending in the developed world, the understanding of these defects has become essential.2,3
Dedicated to the early pioneers in SPS, particularly to Drs. Eberhard F. Mammen (1930–2008) and Rodger L. Bick (1943–2008).
published online June 9, 2014
Issue Theme A Short History of Thrombosis and Hemostasis: Part I (40th Year Celebratory Issue); Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).
Copyright © 2014 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-0034-1381235. ISSN 0094-6176.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Peter Kubisz, MD, DSc1 Guillermo J. Ruiz-Argüelles, MD, FRCP (Glasg), MACP2,3,4 Pavol Holly, MD, PhD1 Guillermo J. Ruiz-Delgado, MD2,3
SPS is thought, according to the present data and at least by a few investigators, to be the most common inherited prothrombotic platelet defect and thus likely to be of the greatest clinical importance. The primary aim of this review is to summarize the past 35 years of the research into SPS and thus provide a brief historical account of SPS with emphasis given on the most relevant studies. Second, we aim to point out the unresolved issues and outline the trends in which the future research is likely to continue.
Historical Overview of Sticky Platelet Syndrome From the Discovery of Platelets to Discovery of Related Qualitative Disorders Platelets as separate components of blood were recognized in the late 19th century in the pioneering studies of Bizzozero4 and Osler,5 their first description dating back to 1873. It is of interest that both authors gave not only the morphological description of platelets but correctly recognized their involvement in blood clotting. Furthermore, in his pathological studies from the 1880s, Osler provided evidence for the participation of platelets in human thrombotic disease, as he identified these small cells in white thrombi formed on atherosclerotic plaques, in vegetations on heart valves, and in aortic aneurysms.6 The role of platelets in hemostasis was further proved by several clinical studies, such as the ones published by Hayem in 19007 and Duke in 1910.8 Through the observation of patients with thrombocytopenia, Hayem and Duke showed that platelet count was inversely related to bleeding in humans and its rapid cessation could be achieved with the increase in platelet count by the means of blood transfusion. Although quantitative changes—namely thrombocytopenia of various causes—were identified in the 1880s as the first hemostatic defects related to platelets,9,10 the description of the first qualitative disorder followed relatively soon, only a few years, later—being May–Hegglin anomaly—as described by May in 1909.11 The first quantitative defects to be described were—unsurprisingly—those characterized by unique morphological features of platelets (May–Hegglin anomaly, Bernard–Soulier syndrome) or disturbances in coagulation tests established in that time (e.g., clot retraction— Glanzmann thrombasthenia).10 The deeper insight in the platelet morphology and physiology were provided by the works of Bernard, Caen, Roskam, Soulier, and others, together with the development of specialized laboratory methods— glass bead platelet retention assay by Hellem and its modifications, turbidimetric platelet aggregometry by Born and O’Brien, and new analytic methods in biochemistry. These all took place from the 1920s to the 1960s, and were crucial for the better understanding of the processes involved in primary hemostasis and platelet activation, as well as for the description of other platelet defects.9,10 Among the tests introduced, the turbidimetric platelet aggregometry developed independently by Born12 and O’Brien13 in 1962 became of great use. This principally simple and reproducible technique, based on
Kubisz et al.
the continuous recording of the transmission of light through a cuvette containing stirred platelets at a constant temperature, allowed for the characterization of the platelet effects of the different agonists, including ADP and EPI. It revealed specific patterns of aggregation after addition of different agonists and enabled the differential diagnosis and further characterization of several qualitative platelet disorders. As mentioned earlier, qualitative platelet disorders were identified relatively soon after the initial descriptions of platelet function—in the early 20th century. Although the role of platelets in both thrombotic and bleeding disorders was recognized almost immediately after their morphological description, the clinical research in this field was rather one-sided, focused predominantly on disorders manifested with increased bleeding. From the beginning of the 20th century, great effort, research time, and foundations were invested into the characterization of hemorrhagic disorders, whereas prothrombotic ones were recognized much later and, in fact, never really “hit the spotlight.” Whereas, Glanzmann thrombasthenia and Bernard–Soulier syndrome, two most widely known qualitative bleeding platelet disorders, were initially described in 191814 and 1948,15 respectively, and were preceded or followed by the identification of a few other bleeding thrombocytopathies,9,10 the publication of the first work dedicated to the prothrombotic qualitative platelet disorder—the one that would later become known as SPS— dated back to only 1979 (►Fig. 1).16
The Discovery of SPS: From Its Initial Description to Full Clinical Picture and Diagnostic Criteria In 1979, al-Mefty et al described 22 patients with transient ischemic attack (TIA), all of whom showed on repeated testing an increased platelet adhesion and/or aggregation.16 No other hemostatic disorder (known at that time), as well as no common cause of central nervous system ischemia (e.g., atherosclerotic cerebral vascular disease, cardiac source of emboli, migraine, arteritis, or collagen disease) were identified in any of the subjects. al-Mefty suggested that the platelet hyperaggregability could be the underlining cause of TIA in those individuals. The idea was supported by his observation that the administration of an antiplatelet agent—acetylsalicylic acid (ASA) led to the rapid cessation of the symptoms, whereas its discontinuation led in some cases to their recurrence. He concluded that there was a specific group of patients with TIA in whom the abnormality of platelet function was a sole cause of the event. In 1983, Holiday et al presented a similar clinical observation at the 9th International Joint Conference on Stroke and Cerebral Circulation in Arizona in a group of patients with ischemic stroke or TIA and platelet hyperaggregability after low concentrations of EPI and/or ADP.17 Holiday postulated this condition as a distinct clinical syndrome and suggested the term SPS to emphasize the underlining defect of platelet aggregation. However, several issues, particularly etiology and epidemiological data, remained unclear at that time. Surprisingly, the earlier mentioned reports did not lead to the expected great interest in platelet hyperaggregability. In the next 20 years, a rather limited number of Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
527
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
Fig. 1 Timeline of important events related to SPS. ADP, adenosine diphosphate; ASA, acetylsalicylic acid (aspirin); EPI, epinephrine; PLT, platelet; SNP, single nucleotide polymorphism; SPS, sticky platelet syndrome; TE, thromboembolism; TIA, transient ischemic attack; VKA, vitamin K antagonists.
investigators published case reports or small retrospective series of patients with platelet hyperaggregability to ADP and/or EPI, no other hemostatic defect, and thrombotic events.18–28 SPS has been found in individuals who suffer not only central nervous system ischemia18–21 but also a broad spectrum of thrombotic events; both arterial and venous thromboses have been reported, although the arterial events have been observed more frequently.22–28 The thrombotic events associated with SPS include angina pectoris and myocardial infarction (MI),19 thrombosis of retinal vessels,20 fetal loss and growth retardation,28 deep venous thrombosis, and pulmonary embolism.23,24 Most of the studies published in the 1980s and 1990s were limited in the number of patients, retrospective in design, and in general add little to the knowledge of the syndrome past its clinical manifestation. However, the works of two investigators—Mammen and Bick—and their groups—did add important data for further understanding and definition of the syndrome. Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
The observations made by Mammen, one of the original coworkers of Holiday, were particularly important for the more precise definition of SPS. Within a decade after Holiday’s report, Mammen et al collected extended clinical data that enabled him to outline detailed characteristics, classification and diagnostics of the syndrome. In 1984, he treated a young woman who suffered from MI during the third semester of her first pregnancy. An extensive laboratory testing failed to reveal any hemostatic abnormalities except for increased in vitro platelet aggregation after both ADP and EPI. While analyzing the patient’s history, Mammen discovered that her mother and 18-year-old brother suffered from arterial thrombotic events as well—the mother had MI during one of her pregnancies and the brother had unexplained repeated attacks of angina pectoris despite normal coronary arteries on angiography.25 On the basis of this case, Mammen came up with the idea that the syndrome could be found not only in patients with stroke but also in others who suffered from thrombotic events, be inherited in an autosomal pattern
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
528
and behind otherwise unexplained thrombotic events, especially in young individuals without severe risk factors. Interestingly, he noted “stressful situations” as a provoking factor for the thrombosis.25 In the following years, Mammen et al identified numerous patients with proven platelet hyperaggregability by laboratory testing and thromboembolic events—as well as a few other families with several affected members and generations. His experience with tens of cases was summarized in several articles published from the mid1990s to 2003 and enabled him to propose clearly defined laboratory and clinical criteria for the syndrome (►Table 1).21,25,26 These criteria were respected and used as a standard in all other subsequent works on SPS. On the basis of the pattern of platelet aggregation, Mammen identified two types of the syndrome: Type I, characterized by hyperaggregability after both ADP and EPI, and Type II, characterized by hyperaggregability after EPI only, with this being more frequent. The classification, however, was based only on laboratory characteristics and Mammen did not observe any relation of SPS types to clinical manifestation, treatment, or course. As for the treatment, he did observe an excellent efficacy of ASA—even in low doses (range, 80–100 mg/day)—in most of the patients, confirming al-Mefty’s initial findings. The work of Mammen was further expanded and completed by Bick.26–28 He confirmed Mammen’s conclusions on diagnostics and, based on his own observation, added the least frequent Type III—hyperaggregability after ADP only—to the syndrome’s classification.26 In accordance with Mammen, he did not confirm any relation of the laboratory-defined types (Types I, II, or III) to clinical or therapeutic issues. Bick was among the first to note SPS in patients with venous TE (VTE)26; he also confirmed the good efficacy of low-dose ASA and recommended it as the firstchoice treatment. His further work focused on two problems —on the role of the syndrome in the subpopulations of patients with unexplained thromboembolic events (e.g., unprovoked thrombosis) and women with child-bearing issues.
Kubisz et al.
He showed that SPS was frequent in both the groups. In the study of 153 patients with unexplained thromboembolic events, he found SPS in 17.6%.26 In collaboration with Hoppensteadt, he showed that a significant number of women with recurrent miscarriage—18.2% of 351 tested individuals in his cohort—fulfilled the criteria of SPS.28 He thus provided a strong clinical evidence for the relation of SPS to fetal loss.28 On the basis of his analyses of the largest patient cohorts to date, he concluded that SPS was likely to be, at least in the populations with unexplained thrombotic events and of white origin (the origin of his groups), one of the most frequent thrombophilias, second only to the resistance to activated protein C (APC-R), and advocated for its wider testing.26,27 Besides these two leading investigators, some interesting features of the syndrome were noted by other researchers as well. In 1998, Chittoor et al reported a case of a 30-year-old woman, who initially suffered from the thrombosis of the superior sagittal sinus manifested as sudden disturbances of sight.24 Anticoagulation with warfarin was initiated and despite being properly managed with the international normalized ratio kept in the therapeutic range, the patient suffered from recurrent deep venous thrombosis of the lower extremities 7 and 10 months later, while still on anticoagulant treatment. The defect of platelet aggregation was identified only after the three earlier mentioned thrombotic events. Warfarin was discontinued and alternate treatment with ASA was initiated. During the 2 subsequent years, while on ASA, the patient had no new episode of TE. The ineffectiveness of anticoagulation and the alternate surprisingly effective treatment and prophylaxis with antiplatelet drugs have since also been observed by others.29–31 The inability of standard anticoagulants to directly influence platelet aggregation is believed to be the most plausible explanation of this phenomenon. In 1999, Chaturvedi and Dzieczkowski were first to describe the occurrence of SPS together with other inherited thrombophilic disorder in the same individual.32 Whereas all
Table 1 Diagnostic criteria for SPS according to Mammen25,26 Platelet aggregation after activation with ADP a
EPI
Concentration of reagent (µM)
0.58
1.17
2.34
0.55
1.1
11.0
Normal rangeb (% aggregation)
0–12
2–36
7.5–55
9–20
15–27
39–80
Diagnostic criteria Suggestive diagnosis:
• History of TE and hyperaggregability to only 1 conc. of 1 reagent
Firm diagnosis:
• History of TE and hyperaggregability to 2 conc. of 1 reagent • History of TE and hyperaggregability to 1 conc. of both reagents • History of TE and hyperaggregability to only 1 conc. of 1 reagent, repeatedly tested
Abbreviations: ADP, adenosine diphosphate; EPI, epinephrine; TE, thromboembolism. Adapted from Mammen.25,26 a The given concentrations were proposed by Mammen for light transmission aggregometry and were used in the majority of to-date published works. b Only informative (based on the authors’ own experience) should be determined within each laboratory. Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
529
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
previous reports found SPS in patients without any other hemostatic disturbances, they described a case of a young woman with recurrent stroke and combined thrombophilia— protein S deficiency, APC-R caused by FV Leiden heterozygosity and SPS. The concomitant occurrence of SPS with other well-defined thrombophilias (elevated factor VIII, antiphospholipid syndrome, prothrombin G20201A, and hyperhomocysteinemia) were subsequently reported.29,33–37 In fact, as shown by Ruiz-Argüelles et al, most patients with SPS phenotype might display other thrombophilic conditions, both inherited and acquired. Thus, the coexistence of SPS with other conditions may be required in some cases for the development of vaso-occlusive episodes and clinical manifestation, in accordance with the concept of multifactorial thrombophilia.37
The Past 10 Years of SPS Research: What Has It Been Able to Add? In general, the research of SPS in the first years of the new millennium could be divided into two main directions. One group of investigators focused on providing further data on the clinical presentation and treatment, whereas the second group took greater interest into the pathophysiology of the syndrome. In the past decade, more case reports and case series, providing an ever increasing evidence on the clinical picture,29–35,37–49 treatment50 or familial occurrence and autosomal trait of inheritance,36,51 were published. The presented clinical data provided further support for the previous observations but add no new characteristics or treatment strategies with the exception of the manuscripts written by El-Amm et al,34 Mühlfeld et al,40 Yagmur et al,45 Lewerenz et al,33 Moncada et al,49 and Velázquez-Sánchezde-Cima et al.50 El-Amm et al, Mühlfeld et al, and Yagmur et al described platelet hyperaggregability in a new clinical setting—in the patients undergoing hemodialysis or renal transplant recipients with thrombotic complications or impaired function of the graft. The results of Yagmur et al are particularly worth mentioning. They evaluated platelet aggregation after EPI in 30 hemodialysis patients and 34 renal transplant recipients and found a surprisingly high prevalence of SPS phenotype— in 67 and 82%, respectively—in those with subsequent thromboembolic events. The authors suggested that the testing of platelet hyperaggregability may supplement the assessment of thromboembolic complications in patients with chronic kidney disease.45 Lewerenz et al and Moncada et al reported cutaneous changes—atrophy blanche, livedo reticularis, erythema nodosum, Raynaud phenomenon, and livedoid vasculopathy—in individuals with the SPS phenotype.33,49 As for the treatment, most of the physicians have been following the example of Mammen and Bick and using ASA as the drug of choice. The report from Velázquez-Sánchez-deCima et al on their experience with ASA, clopidogrel or the concomitant use of both agents in 55 patients with SPS is thus innovative and is the first prospective study of the treatment in SPS.50 They observed an excellent efficacy of both ASA and Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
the combination therapy with ASA and clopidogrel in the prevention of rethrombosis. Their results provided broader clinical data on clopidogrel and showed that the drug might be of use in this setting. So far, most of the data on SPS therapy were taken from the patients who received ASA only; the use of other antiplatelet agents was scarce and limited to few individual case reports.23,40,44 From the initial descriptions, the familial occurrence of SPS was noted. Thus, the syndrome has been regarded, at least in a significant proportion of affected individuals, as a hereditary disorder. Despite the clear clinical definition and strong evidence of familial occurrence, the exact genetic cause of SPS has remained unidentified. Mammen suggested that the defects of membrane platelet glycoproteins (GP) involved in their activation and subsequent actions were likely behind the syndrome.22 However, he was unable to identify any specific genetic changes. Kubisz et al were able to show that the pathophysiology of SPS was indeed related to platelet activation processes. They found the increased surface expression of CD62 and CD51—neoantigens expressed only after platelet activation—in SPS patients in the “calm” state (e.g., outside of acute thromboembolic event) in comparison to normal population.52 In the late 1990s and the 2000s, the results of several genetic analyses suggested the link between the certain single nucleotide polymorphisms (SNPs) of platelet GP and platelet hyperaggregability (increased aggregation after EPI in the carries of allele A2 of GpIIIa PLA A1/A2),53 risk of thrombotic events such as cardiovascular disease, MI, or stroke (increased risk in the carriers of certain SNPs of GpVI or allele A2 of GpIIIa PLA A1/A2, decreased risk in the carries of allele A of SNP Gas6 c. 834 þ 7G > A)54–57 or regulation of platelet response to physiological agonists (GP6 locus).58 The identification of genetic changes of GpIIIa, Gas6 protein, and GpVI as factors influencing platelet aggregation made their genes promising targets in the search for the cause of SPS. In the last years, two investigators—Ruiz-Argüelles et al and Kubisz et al—and their groups became interested in this particular field. However, the results they published so far failed to identify a single genetic defect responsible for SPS or to show a consistent relation of genetic changes in GpIIIa, Gas6 protein, and GP6 genes to SPS or its types.59–64 Thus, the genetic background has yet to be revealed.
Present Understanding of SPS: Where We Currently Stand On the basis of the earlier discussed to-date published studies, the present understanding of SPS can be summarized as follows. SPS is defined by its clinical and laboratory characteristics, with the criteria originally established by Mammen still in use (►Table 1). SPS is a thrombophilic qualitative platelet disorder with familial occurrence and autosomal dominant trait (although its presence among relatives is not a condition for making the diagnosis and is not seen in all patients), characterized by increased in vitro platelet aggregation after low concentrations of ADP and/or EPI. The syndrome is associated with arterial thrombosis, pregnancy complications such as fetal growth retardation and
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
530
loss, and VTE, though the latter is less frequent. Furthermore, SPS might be associated with an impaired graft function in renal transplantation. The clinical presentation of SPS can have several distinct features. The first thrombotic event usually occurs in patients younger than 40 years and with or without acquired risk factors, such as pregnancy, puerperium, or exogenous estrogen use. Once the syndrome shows family occurrence, both genders are affected. Commonly used anticoagulants such as vitamin K antagonists are usually inefficient in the treatment and prophylaxis of thromboembolic events and their use may result in the recurrence of thrombosis. Antiplatelet agents, particularly ASA, are very effective both in treatment and prevention of thrombosis; even low-dose ASA (range, 80–100 mg/day) leads in the majority of patients to the normalization of hyperaggregability on repeated testing.50 The experience with other antiplatelet agents is limited, although recent clinical evidence supports the use of clopidogrel.50 The few patients with SPS that display aspirin refractoriness can be effectively treated with clopidogrel; accordingly, it may be advisable to retest for platelet hyperaggregability after antiplatelet drugs have been started. SPS can occur in a considerable number of patients displaying other thrombophilic conditions, so the screening of other common thrombophilias should not be neglected. According to aggregation pattern, three types of the syndrome can be identified, although this subclassification has no known clinical or therapeutic consequences. Despite several studies focused on SNPs of several platelet GPs (GpIIIa, Gas6 protein, or GpVI), the exact genetic defect responsible for the syndrome remains unknown.
Open Issues and Future Perspectives Although the clinical presentation and laboratory findings in SPS have been described in detail, several issues remain unresolved, most prominently in pathophysiology, epidemiology, and treatment of the syndrome.
Pathophysiology SPS is usually referred to as an inherited platelet disorder. As shown by several authors, the familial occurrence of the syndrome is not uncommon, with an autosomal trait of inheritance and infliction of both women and men. However, there are several unclear issues, once one tries to describe the inheritance pattern in greater detail. First, as the underlining genetic defect is not known, it is impossible to decide whether the pattern is dominant or recessive. Second, in several published family pedigrees, the same type of the syndrome may not be present in all members and generations within the affected family.51 Third, additional affected relatives or descendants were not identified for all patients diagnosed with SPS and on occasion the family history might be completely negative. The discrepancies in inheritance pattern, together with the failure of the genetic studies to identify a single underlining genetic defect and laboratory heterogeneity of the syndrome with three clearly distinct types might suggest, in our opinion, two explanations. First, SPS might have a multifactorial
Kubisz et al.
genetics—various mutations of the same or even various genes resulting in similar phenotypes. Second, because the diagnosis of SPS is made solely on the clinical (thromboembolic event) and laboratory criteria (platelet hyperaggregability) and not on genetic testing, individuals with both inherited and acquired changes of platelet aggregation may be included in the currently diagnosed patient groups. There is growing evidence, for example, that the same laboratory phenotype as in inherited SPS could be seen in certain metabolic (diabetes mellitus and atherosclerosis) or inflammatory (sepsis and systemic immune disorders) diseases.65,66 In this context, a recent publication from Yagmur et al, identifying a surprisingly high number of individuals with platelet hyperaggregability with EPI among patients with chronic renal disease undergoing hemodialysis or renal transplantation, is very interesting.45 In our opinion, this scenario might be representative of the “acquired” SPS phenotype. It is therefore likely that the previous studies have included individuals with both the “inherited” and “acquired” forms of platelet hyperaggregability, as their distinction was not, to our knowledge, rigorously addressed therein. The separation of these two entities and the initiation of new clinical studies with precisely chosen participants will be crucial for the better understanding of the syndrome and elucidation of the conflicting genetic results. It is also critical to standardize the methods used to assess the SPS phenotype. ►Table 1 shows the diagnostic criteria proposed by Mammen et al20,25 as well as the laboratory studies needed to define the condition. Ideally, all laboratories should employ comparative concentrations of aggregating agents to conduct the tests and to assess the patterns representative of normal individuals and abnormal aggregation to a lower concentration of agonist; this will improve comparability of results between laboratories.
Epidemiology Although a decent number of scientific reports on SPS have been published to date, the epidemiological data are surprisingly limited. The limitation might have been caused, at least partially, by the lack of recognition of the disorder and scepticism shared by a significant proportion of clinicians, as discussed later. The exact prevalence of the syndrome in the whole population as well as in subpopulations with thrombotic events or even among patients with a distinct localization of thrombosis (e.g., stroke) is not known. Most of the reports were individual case reports or small case series in design and thus limited in number of patients. In those cases when a larger cohort was evaluated, only selected proportion of patients with TE—almost exclusively with unexplained events—were involved. The criteria used for the selection of participants were not clearly stated in most of the works. Second, almost all to-date studies analyzed the individuals of white origin; the data on other human races are therefore limited. Even the little data available so far show striking racial differences. For example, the distribution of SPS subtypes may be different in distinct populations and does not seem to be related to the severity of the disease nor to its Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
531
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
clinical presentation. Type II is the most frequent variant of SPS in white populations, whereas Type I is the most frequent variant in Mexican mestizos.36,37,49,58,67 In Mexican mestizos, the SPS phenotype is the second most frequent inherited cause of thrombophilia.68 The knowledge of the epidemiological data which have to be delivered by new studies might be helpful in decisions on several issues: whether the testing of SPS should be included in the standard thrombophilia screening, whether the patients with certain localization of thrombosis should be tested in advance, or whether the testing of the extended family of the affected individuals is likely to identify a reasonable number of new cases and be economically justified. At present, most of these questions have to be answered by the treating physician individually, on a case-to-case basis.
Treatment It has been repeatedly shown by various authors that antiplatelet agents, especially ASA, are efficient both in treatment and prevention of thrombosis in SPS. However, several therapeutic problems, some rather similar to other thrombophilic disorders, were not fully covered in the published studies. First, the data on the antiplatelet agents other than ASA, and in relation to dosing and efficacy, are limited. It has been assumed that they should be equally effective as ASA in the doses used in other conditions that required platelet inhibition, but the clinical evidence is scarce (in the case of clopidogrel) or missing (in the case of other agents). The laboratory evaluation and monitoring of the antiplatelet treatment should also be assessed. Second, as in other thrombophilias, the duration of the antiplatelet treatment, the treatment of asymptomatic individuals including children, screening of asymptomatic relatives, and the prophylaxis in risk situation such as pregnancy or invasive procedures are among the controversial questions commonly faced by physicians in routine practice but with little or no clinical evidence in terms of reasonably large retrospective studies or randomized trials. Third, there are no universal recommendations for the treatment of patients with SPS and concomitant thrombophilic disorder(s). The presence of the other hemostatic defect(s) usually leads to the administration of the combination of antithrombotics (antiplatelet agents with anticoagulants such as vitamin K antagonists) with individualized dosing. However, none of the published studies have focused on this specific subgroup and thus the clinical evidence that will justify this practice is lacking. These fundamental therapeutic issues were not intentionally addressed in previous works. Their answering, however, is essential for the rationale and adequate therapeutic management and represents, undoubtedly, the challenge for future clinical trials.
Scepticism Regarding Sticky Platelet Syndrome The recognition of SPS as a true entity has prompted the development of both promoters and opponents to the Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
concept. Up to now, the lack of a definite molecular basis for the condition has been a major obstacle for its acceptance as a distinct entity and several sceptical scientists are still reluctant to consider this disease as a true distinct clinicopathological entity. Some experts still consider the aberrant platelet aggregation responses seen in this condition as laboratory artifacts.
Conclusion We sincerely hope that this article will result in the development of additional interest in other investigators who could eventually contribute to the better understanding and acceptance of the syndrome, its pathophysiology and treatment, with the goal of helping patients afflicted by thrombophilia, currently one of the leading causes of death in developed societies.
Acknowledgments The work was supported by the project APVV 00–222–11, Vega 1/0016/12, and Martin Center of Biomedicine (Biomed Martin), ITMS: 26220220187.
Declaration of Conflicting Interests The authors state that they have no conflict of interest to declare with respect to the research, authorship, and publication of this article.
References 1 Nurden AT, Freson K, Seligsohn U. Inherited platelet disorders.
Haemophilia 2012;18(Suppl 4):154–160 2 Cohen AT, Agnelli G, Anderson FA, et al; VTE Impact Assessment
3 4
5 6 7 8 9 10 11 12 13 14
Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007;98(4):756–764 Ingall T. Stroke—incidence, mortality, morbidity and risk. J Insur Med 2004;36(2):143–152 Bizzozero J. Über einen neuen Formbestandteil des Blutes und dessen Rolle bei der Thrombose und der Blutgerinnung. Virchow’s. Arch Pathol Anat Physiol Klin Med 1882;90:261–332 Osler W. An account of certain organisms occurring in the liquor sanguinis. Proc R Soc Lond 1874;22:391–398 Osler W. On certain problems in the physiology of the blood corpuscles. The Medical News 1886;48:421–425 Hayem G. Leçons sur les maladies du sang. Paris: Masson; 1900 Brinkhous KMWW. W. W. Duke and his bleeding time test. A commentary on platelet function. JAMA 1983;250(9):1210–1214 de Gaetano G. Historical overview of the role of platelets in hemostasis and thrombosis. Haematologica 2001;86(4):349–356 Coller BS. Historical perspective and future directions in platelet research. J Thromb Haemost 2011;9(Suppl 1):374–395 May R. Leokozyteneinschlusse. Deutsch Arch Klin Med 1909; 96:1–6 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–929 O’Brien J. Platelet aggregation: Part II Some results from a new method of study. J Clin Pathol 1962;15(5):452–455 Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis 2006;1:10
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
532
Kubisz et al.
15 Bernard J. History of congenital hemorrhagic thrombocytopathic
37 Ruiz-Argüelles GJ, López-Martínez B, Valdés-Tapia P, Gómez-Ran-
dystrophy. Blood Cells 1983;9(2):179–193 al-Mefty O, Marano G, Raiaraman S, Nugent GR, Rodman N. Transient ischemic attacks due to increased platelet aggregation and adhesiveness. Ultrastructural and functional correlation. J Neurosurg 1979;50(4):449–453 Holiday PL, Mammen E, Gilroy J. Sticky platelet syndrome and cerebral infarction in young adults. Paper presented at: The Ninth International Joint Conference on Stroke and Cerebral Circulation; 1983; Phoenix, AZ Warrier I, Nigro M, Hillman C, et al. Platelet activation associated with stroke migraine in children. Thromb Haemost 1991;65:772 Berg-Dammer E, Henkes H, Trobisch H, Kühne D. Sticky platelet syndrome: a cause of neurovascular thrombosis and thromboembolism. Interv Neuroradiol 1997;3(2):145–154 Mammen EF, Barnhart MI, Selik NR, Gilroy J, Klepach GL. “Sticky platelet syndrome”: a congenital platelet abnormality predisposing to thrombosis? Folia Haematol Int Mag Klin Morphol Blutforsch 1988;115(3):361–365 Frenkel EP, Mammen EF. Sticky platelet syndrome and thrombocythemia. Hematol Oncol Clin North Am 2003;17(1):63–83 Rubenfire M, Blevins RD, Barnhart M, Housholder S, Selik N, Mammen EF. Platelet hyperaggregability in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 1986;57(8):657–660 Bick RL. Sticky platelet syndrome: A common cause of unexplained arterial and venous thrombosis. Clin Appl Thromb Hemost 1998; 4:77–81 Chittoor Elsehety AE, Roberts GF, Laughlin WR. Sticky platelet syndrome: a case report and review of the literature. Clin Appl Thromb Hemost 1998;4:280–284 Mammen EF. Ten years’ experience with the “Sticky platelet syndrome”. Clin Appl Thromb Hemost 1995;1:66–72 Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost 1999;25(4):361–365 Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects. Hematol Oncol Clin North Am 2003;17(1):9–36 Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost 2005;11(1):1–13 Fodor M, Facskó A, Berényi E, Sziklai I, Berta A, Pfliegler G. Transient visual loss triggered by scuba diving in a patient with a petrous epidermoid and combined thrombotic risk factors. Pathophysiol Haemost Thromb 2007;36(6):311–314 Kannan S. Recurrent arterial thrombosis in a young male: sticky platelet syndrome. Internet J Hematol 2008;4(1):4 Sand M, Mann B, Bechara FG, Sand D. Sticky platelet syndrome type II presenting with arterial microemboli in the fingers. Thromb Res 2009;124(2):244 Chaturvedi S, Dzieczkowski JS. Protein S deficiency, activated protein C resistance and sticky platelet syndrome in a young woman with bilateral strokes. Cerebrovasc Dis 1999; 9(2):127–130 Lewerenz V, Burchardt T, Büchau A, Ruzicka T, Megahed M. Livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome [in German]. Hautarzt 2004; 55(4):379–381 El-Amm JM, Andersen J, Gruber SA. Sticky platelet syndrome: a manageable risk factor for posttransplant thromboembolic events. Am J Transplant 2008;8(2):465 Bojalian MO, Akingba AG, Andersen JC, et al. Sticky platelet syndrome: an unusual presentation of arterial ischemia. Ann Vasc Surg 2010;24(5):e1–e6 Ruiz-Argüelles GJ, Alarcón-Urdaneta C, Calderón-García J, RuizDelgado GJ. Primary thrombophilia in México VIII: Description of five kindreds of familial sticky platelet syndrome phenotype. Rev Hematol Mex 2011;12(2):73–78
gel JD, Reyes-Núñez V, Garcés-Eisele J. Primary thrombophilia in Mexico. V. A comprehensive prospective study indicates that most cases are multifactorial. Am J Hematol 2005;78(1):21–26 Kahles H, Trobisch H, Kehren H. Disseminated coronary occlusions and massive pulmonary embolism in a 40-year-old woman [in German]. Dtsch Med Wochenschr 2006;131(13):672–675 Randhawa S, Van Stavern GP. Sticky platelet syndrome and anterior ischaemic optic neuropathy. Clin Experiment Ophthalmol 2007; 35(8):779–781 Mühlfeld AS, Ketteler M, Schwamborn K, et al. Sticky platelet syndrome: an underrecognized cause of graft dysfunction and thromboembolic complications in renal transplant recipients. Am J Transplant 2007;7(7):1865–1868 Mears KA, Van Stavern GP. Bilateral simultaneous anterior ischaemic optic neuropathy associated with Sticky Platelet Syndrome. Br J Ophthalmol 2009;93(7):885–886, 913 Loeffelbein DJ, Baumann CM, Mücke T, Wolff KD, Hölzle F, Kesting MR. Sticky platelet syndrome as a possible cause for free flap failure—a case report. Microsurgery 2010;30(6):466–468 Rac MW, Minns Crawford N, Worley KC. Extensive thrombosis and first-trimester pregnancy loss caused by sticky platelet syndrome. Obstet Gynecol 2011;117(2 Pt 2):501–503 Gehoff A, Kluge JG, Gehoff P, et al. Recurrent strokes under anticoagulation therapy: Sticky platelet syndrome combined with a patent foramen ovale. J Cardiovasc Dis Res 2011;2(1):68–70 Yagmur E, Frank RD, Neulen J, Floege J, Mühlfeld AS. Platelet hyperaggregability is highly prevalent in patients with chronic kidney disease: an underestimated risk indicator of thromboembolic events. Clin Appl Thromb Hemost 2013(e-pub ahead of print) Darulová S, Samoš M, Sokol J, et al. Sticky platelets syndrome in a young patient with massive pulmonary embolism. Am J Case Rep 2013;14:169–172 Tekgündüz E, Demir M, Akyol Erikçi A, Akpınar S, Oztürk E, Kırkızlar O. Sticky platelet syndrome in patients with uninduced venous thrombosis. Turk J Haematol 2013;30(1):48–52 Kubisz P, Stasko J, Holly P. Sticky platelet syndrome. Semin Thromb Hemost 2013;39(6):674–683 Moncada B, Castillo-Martínez C, Ruiz-Argüelles GJ, Valdés-Tapia P, Arenas-Velázquez E. Sticky platelets syndrome: a frequent cause of primary thrombophilia. J Invest Dermatol 2013;133(Suppl 1):S180 Velázquez-Sánchez-de-Cima S, Zamora-Ortiz G, Hernández-Reyes J, et al. Primary thrombophilia in Mexico X: a prospective study of the treatment of the sticky platelet syndrome. Clin Appl Thromb Hemost 2013 (e-pub ahead of print) Šimonová R, Bartosová L, Chudý P, et al. Nine kindreds of familial sticky platelet syndrome phenotype. Clin Appl Thromb Hemost 2013;19(4):395–401 Staško J, Bartošová L, Mýtnik M, Kubisz P. Are the platelets activated in sticky platelet syndrome? Thromb Res 2011;128(1):96–97 Feng D, Lindpaintner K, Larson MG, et al. Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 1999;19(4):1142–1147 Cole VJ, Staton JM, Eikelboom JW, et al. Collagen platelet receptor polymorphisms integrin alpha2beta1 C807T and GPVI Q317L and risk of ischemic stroke. J Thromb Haemost 2003;1(5):963–970 Ollikainen E, Mikkelsson J, Perola M, Penttilä A, Karhunen PJ. Platelet membrane collagen receptor glycoprotein VI polymorphism is associated with coronary thrombosis and fatal myocardial infarction in middle-aged men. Atherosclerosis 2004;176(1):95–99 Muñoz X, Obach V, Hurtado B, de Frutos PG, Chamorro A, Sala N. Association of specific haplotypes of GAS6 gene with stroke. Thromb Haemost 2007;98(2):406–412 Shaffer JR, Kammerer CM, Dorn J, et al. Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians. Nutr Metab Cardiovasc Dis 2011;21(8):546–552
16
17
18 19
20
21 22
23
24
25 26 27
28
29
30 31
32
33
34
35
36
38
39
40
41
42
43
44
45
46
47
48 49
50
51
52 53
54
55
56
57
Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
533
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Sticky Platelet Syndrome
Sticky Platelet Syndrome
Kubisz et al.
58 Johnson AD, Yanek LR, Chen MH, et al. Genome-wide meta-
63 Sokol J, Biringer K, Škereňová M, et al. Platelet aggregation
analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet 2010;42(7):608–613 Kubisz P, Ivankov J, Hollý P, Staško JN, Musiał J. The glycoprotein IIIa PL(A1/A2) polymorphism—a defect responsible for the sticky platelet syndrome? Clin Appl Thromb Hemost 2006; 12(1):117–119 Ruiz-Argüelles GJ, Garcés-Eisele J, Camacho-Alarcón C, et al. Primary thrombophilia in Mexico IX: the glycoprotein IIIa PLA1/ A2 polymorphism is not associated with the sticky platelet syndrome phenotype. Clin Appl Thromb Hemost 2013;19(6):689–692 Kubisz P, Bartosová L, Ivanková J, et al. Is Gas6 protein associated with sticky platelet syndrome? Clin Appl Thromb Hemost 2010; 16(6):701–704 Kubisz P, Ivanková J, Škereňová M, Staško J, Hollý P. The prevalence of the platelet glycoprotein VI polymorphisms in patients with sticky platelet syndrome and ischemic stroke. Hematology 2012; 17(6):355–362
abnormalities in patients with fetal losses: the GP6 gene polymorphism. Fertil Steril 2012;98(5):1170–1174 Kotuličová D, Chudý P, Škereňová M, Ivanková J, Dobrotová M, Kubisz P. Variability of GP6 gene in patients with sticky platelet syndrome and deep venous thrombosis and/or pulmonary embolism. Blood Coagul Fibrinolysis 2012;23(6):543–547 Vieira de Abreu A, Rondina MT, Weyrich AS, Zimmerman GA. Inflammation. In: Michelson AD, ed. Platelets. 3rd ed. Oxford, UK: Elsevier Inc.; 2013:733–766 Ferreiro JL, Gómez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 2010;7(4):251–259 Ruiz-Argüelles GJ, López-Martínez B, Cruz-Cruz D, Esparza-Silva L, Reyes-Aulis MB. Primary thrombophilia in Mexico III: A prospective study of the sticky platelet syndrome. Clin Appl Thromb Hemost 2002;8(3):273–277 Ruiz-Argüelles GJ, Ruiz-Delgado GJ. Trombofilia. In: Ruiz-Argüelles GJ, Ruiz-Delgado GJ, eds. Fundamentos de Hematología. 5th ed. Ciudad de México: Editorial Médicsa Panamericana; 2014:287–296
59
60
61
62
Seminars in Thrombosis & Hemostasis
Vol. 40
No. 5/2014
64
65
66 67
68
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
534
Copyright of Seminars in Thrombosis & Hemostasis is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
