Primary Thrombophilia XIV: Worldwide Identification of Sticky Platelet Syndrome

Sticky platelet syndrome (SPS) is a prothrombotic platelet disorder characterized by increased in vitro platelet aggregation after activation with low concentrations of adenosine diphosphate and/or epinephrine.[ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ] [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ] [ 53 ] [ 54 ] [ 55 ] [ 56 ] [ 57 ] [ 58 ] [ 59 ] [ 60 ] [ 61 ] [ 62 ] [ 63 ] [ 64 ] [ 65 ] [ 66 ] [ 67 ] Recently, Favaloro and Lippi[ 66 ] provided a commentary on the increasing number of papers published on SPS along the historical timeline, since its initial description in 1988,[ 3 ] and in response an update review was also published in this journal.[ 67 ] As noted in both reports,[ 66 ] [ 67 ] the condition is not recognized by all workers involved in the study for treatment of thrombophilic conditions. One reason to explain the fact that some researchers recognize SPS as a genuine thrombophilic condition whilst other do not is that not everybody employs the same criteria to define the condition. We and others,[ 11 ] [ 53 ] attempting to standardize its investigation, employ the criteria originally described by Mammen et al[ 3 ] to define SPS, and accordingly, our group has been able to show that around 15% of Mexican mestizo persons within the general normal population meet the criteria to identify them as bearers of SPS and that this figure goes up to 60% in Mexican mestizo patients with a clinical marker of inherited thrombophilia. Accordingly, we have been able to gather prospectively a group of 165 Mexican mestizo patients with SPS, 121 of whom (66.7%) display another thrombophilic condition in addition to SPS. Employing the database PubMed, we similarly looked for all entries using the term “sticky platelet,” either in the title and/or in the body of the abstract. The salient features of each publication were then further analyzed. The initial search identified a total of 108 papers. Forty-one of them included the combination of words but did not actually describe SPS and were accordingly discarded; 24 papers comprised reviews about SPS and 43 papers described either cases or series of patients; these latter 43 papers were further analyzed. The first paper describing patients with SPS was identified to be published in 1988, and was authored by Mammen et al.[ 3 ] Since then and until February 2019, as noted above, 67 papers were identified.[ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ] [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ] [ 53 ] [ 54 ] [ 55 ] [ 56 ] [ 57 ] [ 58 ] [ 59 ] [ 60 ] [ 61 ] [ 62 ] [ 63 ] [ 64 ] [ 65 ] [ 66 ] [ 67 ] [ Fig. 1 ] depicts the number of papers published as a cumulative timeline, whereas [ Fig. 2 ] depicts the countries in which these papers were published. It is interesting to note that the country with the largest number of papers published on SPS is the United States with a total of 14, followed by Slovakia with 12, Germany with 8, and México with 6, whereas Hungary, Turkey, Russia, and New Zealand had only 1 publication each. What is also interesting is the absence of reports from most other geographies ([ Fig. 2 ]). Fig. 1 Cumulative frequency distribution curve along time of papers published on the sticky platelet syndrome between 1988 and 2018 inclusive. Fig. 2 Countries in which the sticky platelet syndrome has been described between 1988 and 2018 inclusive. A total of 1,783 patients with SPS have been described and published in these 30 years (1988–2019) of reports. The rate of description of these cases has increased in the last 10 years ([ Fig. 1 ]). The most number of cases have been identified and published in Slovakia ( n = 845), followed by the United States ( n = 451), México ( n = 322), Germany ( n = 88), and Russia ( n = 70). The thromboses identified in these patients were both venous and arterial; in some patients SPS was identified together with another thrombophilic condition, either inherited or acquired. [ Table 1 ] gathers the salient information from all these publications. Most patients (72%) were treated with aspirin and/or other antiplatelet drugs, whereas 27% were given oral anticoagulants or heparin. Table 1 Salient features of the patients with the sticky platelet syndrome who have been described in different countries between 1988 and 2018 inclusive Author Country Year Cases Location of thrombosis Treatment Mammen et al [ 3 ] United States 1988 ? MI Aspirin Berg-Dammer et al [ 4 ] Germany 1997 2 Superior sagittal sinus/middle cerebral artery/left subclavian/left vertebral artery Heparin/aspirin/catheter/thrombolysis Baker and Bick [ 6 ] United States 1999 153 DVT/stroke/MI/retinal vein Aspirin Chaturvedi and Dzieczkowski [ 8 ] United States 1999 1 Acute stroke Heparin/warfarin Bick [ 10 ] United States 2000 21 Recurrent miscarriage Aspirin Weber et al [ 12 ] Germany 2002 34 DVT/retinal vein thrombosis/portal vein thrombosis/pulmonary embolism Heparin/aspirin Frenkel and Mammen [ 15 ] United States 2003 200 Acute stroke, DVT Aspirin 81 mg/d Lewerenz et al [ 17 ] Germany 2004 1 Acute stroke/MI Aspirin Kahles et al [ 21 ] Germany 2006 1 Acute myocardial infarction/pulmonary embolism Abciximab/stent/antiplatelet therapy/t-PA/heparin Kubisz et al [ 20 ] Slovakia 2006 128 Acute stroke/MI/DVT/recurrent miscarriage – Fodor et al [ 23 ] Hungary 2007 1 Left internal carotid artery Aspirin 300 mg/d Mühlfeld et al [ 25 ] United States 2007 3 Renal allograft rejection/colonic microinfarctions/pulmonary embolism/DVT Heparin/aspirin Randhawa and Van Stavern [ 26 ] New Zealand 2007 1 Ischemic optic neuropathy Aspirin 81 mg/d Ruiz-Argüelles et al [ 24 ] Mexico 2007 46 Thrombosis at younger than 40/recurrent thrombosis/thrombosis in unusual sites Aspirin El-Amm et al [ 27 ] United States 2008 3 Renal allograft rejection Aspirin Mears and Van Stavern [ 29 ] United States 2009 1 Ischemic optic neuropathy Aspirin 81 mg/d Sand et al [ 28 ] Germany 2009 1 Cutaneous microembolism on fingers Heparin/aspirin Bojalian et al [ 3 ] United States 2010 1 Popliteal artery/renal and splenic infarction/left axillar artery/left subclavian artery/left internal jugular vein Heparin/embolectomy/aspirin Loeffelbein et al [ 32 ] Germany 2010 1 Venous and arterial flap thrombosis Aspirin Alexandra et al [ 34 ] United States 2011 1 Retinal vein Aspirin Gehoff et al [ 36 ] Germany 2011 1 Acute stroke Aspirin Rac et al [ 35 ] United States 2011 1 Recurrent miscarriage Aspirin 325 mg/d Kotuličová et al [ 40 ] Slovakia 2012 77 Pulmonary embolism/DVT/MI/acute stroke – Kubisz et al [ 38 ] Slovakia 2012 9 2 DVT/4 arterial (acute stroke, MI, arterial thrombosis)/3 both – Sokol et al [ 39 ] Slovakia 2012 27 Recurrent miscarriage Aspirin Darulová et al [ 44 ] United States 2013 1 Pulmonary embolism Alteplase/heparin Ruiz-Argüelles et al [ 47 ] Mexico 2013 100 Thrombosis at younger than 40/recurrent thrombosis/thrombosis in unusual sites Aspirin Šimonová et al [ 46 ] Slovakia 2013 9 Cerebral venous thrombosis/DVT/pulmonary embolism/acute stroke/MI Heparin/aspirin Tekgündüz et al [ 42 ] Turkey 2013 6 History of thrombosis Aspirin 100 mg/d Vasil'ev et al [ 41 ] Russia 2013 70 Thrombosis Heparin/aspirin Castillo-Martínez et al [ 52 ] Mexico 2014 1 Cutaneous limb veins Aspirin 81 mg/d Hayes et al [ 51 ] United States 2014 64 Acute stroke/DVT/MI Aspirin Kubisz [ 48 ] Slovakia 2014 71 Acute stroke – Ruiz-Arguelles [ 50 ] Mexico 2014 95 Thrombosis at younger than 40/recurrent thrombosis/thrombosis in unusual sites Aspirin Alsheekh et al [ 55 ] United States 2015 1 Carotid artery Abciximab/thrombectomy Sokol et al [ 53 ] Slovakia 2015 23 Recurrent miscarriage Aspirin Sokol et al [ 56 ] Slovakia 2015 20 Recurrent miscarriage Aspirin Yagmur et al [ 54 ] Germany 2015 48 TIA/ DVT/pulmonary embolism/renal infarction Heparin/aspirin Ruiz-Delgado et al [ 60 ] Mexico 2017 77 Recurrent miscarriage Aspirin Škereňová et al [ 63 ] Slovakia 2018 37 Recurrent miscarriage Aspirin Sokol et al [ 65 ] Slovakia 2018 84 DVT Aspirin Sokol et al [ 62 ] Slovakia 2018 360 DVT/pulmonary embolism/MI/miscarriage/migraine Aspirin 325 mg/d Solis-Jimenez et al [ 61 ] Mexico 2018 1 Renal allograft rejection (renal infarction) Nephrectomy/aspirin Abbreviations: DVT, deep vein thrombosis; MI, myocardial infarction; t-PA, tissue plasminogen activator. According to several publications, SPS is thought, at least by several investigators, to be the most common inherited prothrombotic platelet defect and thus likely to be of the greatest clinical importance.[ 49 ] The recognition of SPS as a genuine entity has prompted the development of both promoters and opponents to the concept.[ 66 ] [ 67 ] Up to now, the lack of a definite molecular basis for the condition has been a major obstacle for its acceptance by many as a distinct entity and several skeptical scientists remain reluctant to consider this disease as a true distinct clinicopathological entity.[ 49 ] [ 66 ] [ 67 ] On the other hand, unlike plasma-based hemostasis research work, the study of SPS requires fresh patient material and highly meticulous sample collection and handling; as a consequence, the patients under investigation require blood collection at the time of investigation, and then platelet function testing needs to be performed immediately afterwards by experienced personnel. Some hemostasis experts still consider the aberrant platelet aggregation responses seen in this condition as laboratory artifacts[ 49 ]; however, SPS seems to be building up an increasing belief base, if we accept that the increasing publication rate on the topic (66; [ Fig. 1 ]), coupled with the additional information presented here, represents increasing acceptance of SPS as a prothrombotic condition. Taking into account the number of inhabitants in each of the countries which have reported cases of the SPS, it is clear that the countries which have made the most contributions on SPS per number of inhabitants are Slovakia and México; this finding reflects mainly the interest in the condition of groups of scientists living in these two countries, headed by professors Peter Kubisz in Slovakia and Guillermo Ruiz-Argüelles in México.[ 49 ] We hope that the presentation of this information 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, which is currently one of the leading causes of death in developed societies.