A new decade awaits sticky platelet syndrome: where are we now, how do we manage and what are the complications?

INTRODUCTION: Sticky platelet syndrome is a less known platelet function disorder with a familiar occurrence and likely genetic background. Clinically, it is characterized by an increased risk of venous and arterial thromboembolic events and obstetric placenta-mediated complications. The increased aggregation after low-dose ADP and/or epinephrine is its distinctive laboratory feature. Though described for almost 40 years, several issues regarding its etiology, involved pathomechanisms, genetic background, optimal diagnostic and treatment approach remain controversial. AREAS COVERED: The work aims to summarize published studies, the actual definition of the syndrome, and point out its drawbacks. A literature search on Medline, Embase, and archives from EHA congresses was performed (terms: 'sticky platelet syndrome' - 'platelet hyperreactivity' - 'platelet hyperaggregability'). The authors added in their unpublished data. The introductory overview of the present understanding is followed by the discussion of the pathophysiologic, diagnostic, and therapeutic problems. EXPERT OPINION: Despite the growing evidence provided by case reports and series, the lack of robust studies limits the decision-making on diagnostics and management. The diagnostic issues, particularly the standardization of light transmission aggregometry, represent the crucial problem for the broader acceptance of the syndrome.

PLAIN LANGUAGE SUMMARY Sticky platelet syndrome is aplatelet function disorder. It is associated with an increased risk of venous thromboembolism, arterial thrombosis, and obstetric placenta-mediated complications. Increased aggregation after low-dose ADP and/or epinephrine is the defining laboratory feature. Furthermore, afew studies report the familiar occurrence with possible genetic background. Several issues regarding the syndrome remain controversial: its exact etiology, genetics, optimal diagnostic, and treatment approach. These uncertainties provide ground for debate of the syndrome as aunique clinical entity. The review has two goals. Firstly, it summarizes the published studies and the actual definition of the syndrome. Secondly, it tries to point out the open pathophysiologic, diagnostic, and therapeutic problems.

[Platelet activation in lung cancer]. / Activation plaquettaire dans le cancer du poumon.

During primary hemostasis the platelets aggregate to form the platelet thrombus. ADP and thrombin generated by coagulation are the main agonists in platelet aggregation. In a previous study we were able to show that patients with lung cancer had hypercoagulability, hyperfibrinogemia (≥ 6.22 g/L) was predictive of thromboembolic disease at the start of diagnosis before any therapy. In this study, we studied platelet aggregation in these patients in order to demonstrate whether they have hyperaggregability associated with the hypercoagulability demonstrated previously, and this by evaluating abnormalities in primary hemostasis (platelet count and platelet aggregation). One hundred and one patients diagnosed before any therapy and 72 blood donors were included. Agonists used for platelet aggregation are collagen and adenosine diphosphate at low concentrations. Hyperaggregability is observed when blood platelets are stimulated by ADP at different concentrations (p ≤ 0.01). This hyperaggregability is influenced by the histological type and not the development of the cancer, the age of the subjects and the platelet count, it is independent of hyperfibrinogemia and the occurrence of thromboembolic disease. However, an increase in the platelet level is found in patients with hyperfibrinogemia. Patients with lung cancer present platelet activation observed by aggregometry in response to ADP; which is not influenced by hyperfibrinogemia during cancer.

MicroRNA and hyperaggregability of platelets in women with sticky platelet syndrome and pregnancy complications.

AIMS: We aimed to characterize relationship between the expression profiles of platelet miR-96, miR-126 and miR-223 and platelet function examination in patients with sticky platelet syndrome (SPS) and in healthy controls. BACKGROUND: MicroRNAs (miRNA, miR) are a group of small and non-coding RNAs involved in many mechanisms as regulators of post-transcriptional protein expression in platelets. SPS is defined as platelet hyperaggregability after administration of low doses of adenosine diphosphate and/or epinephrine. Clear genetic abnormality of this syndrome is not known yet. METHODS: We examined 45 patients with SPS and 30 healthy volunteers. For functional platelet examination we used light transmission aggregometry, and qRT-PCR was used to determine the expression of the miRNAs. RESULTS: We observed no relationship of the platelet miRNA expression with functional platelet examination in the entire cohort of patients with SPS. However, in a group of patients with SPS and pregnancy complications, we found that the expression of platelet miR-96 (p = 0.009) was up-regulated. CONCLUSION: In spite of the multiple limitations of the study, it can be considered that the increased expression of platelet miR-96 found in a group of patients with SPS and pregnancy complications could be related to the hyperaggregability in these selected patients (Tab. 2, Ref. 31).

Primary Thrombophilia in Mexico XIII: Localization of the Thrombotic Events in Mexican Mestizos With the Sticky Platelet Syndrome.

The sticky platelet syndrome (SPS) is a common cause of both arterial and venous thrombosis, being a dominant autosomal disease with qualitative platelet alterations and familial occurrence. It is characterized by platelet hyperreactivity with increased platelet aggregability in response to low concentrations of platelet agonists: epinephrine, adenosine diphosphate, or both. The clinical manifestations involve venous or arterial thrombosis, recurrent pregnancy loss, and fetal growth retardation. To analyze the localization of the thrombotic episodes in a cohort of Mexican mestizo patients with SPS. Between 1992 and 2016, 86 Mexican mestizo patients with SPS as the single thrombophilic condition were prospectively identified; all of them had a history of thrombosis. There were 15 males and 71 females. The thrombotic episodes were arterial in 26 cases and venous in 60 (70%). Arterial thrombosis was mainly pulmonary thromboembolism, whereas venous thromboses were identified most frequently in the lower limbs. Mexican mestizo population with SPS is mainly female; the type I of the condition is the most frequent; both arterial and venous thrombosis can occur, and they are mainly pulmonary embolism and lower limbs venous thrombosis, respectively.

Platelet abnormalities in nephrotic syndrome.

Nephrotic syndrome (NS) is a common kidney disease associated with a significantly increased risk of thrombotic events. Alterations in plasma levels of pro- and anti-coagulant factors are involved in the pathophysiology of venous thrombosis in NS. However, the fact that the risk of both venous and arterial thrombosis is elevated in NS points to an additional role for blood platelets. Increased platelet counts and platelet hyperactivity have been observed in nephrotic children. Platelet hyperaggregability, increased release of active substances, and elevated surface expression of activation-dependent platelet markers have been documented. The mechanisms underlying those platelet alterations are multifactorial and are probably due to changes in plasma levels of platelet-interfering proteins and lipid changes, as a consequence of nephrosis. The causal relationship between platelet alterations seen in NS and the occurrence of thromboembolic phenomena remains unclear. Moreover, the efficiency of prophylactic treatment using antiplatelet agents for the prevention of thrombotic complications in nephrotic patients is also unknown. Thus, antiplatelet medication is currently not generally recommended for routine prophylactic therapy.

Genetic variations of the GP6 regulatory region in patients with sticky platelet syndrome and miscarriage.

INTRODUCTION: Thrombophilia increases the risk of venous thrombosis during pregnancy and may predispose to gestational vascular complications. OBJECTIVE: The aim of this study is to evaluate the variability of GP6 regulatory regions in a group of patients with platelet hyperaggregability manifested as miscarriage compared with control subjects. METHODS: We examined 27 female patients with platelet hyperaggregability and history of spontaneous abortion and 42 healthy women. Platelet hyperaggregability was established by light transmission aggregometry. We also assessed eight SNPs within the GP6 gene. RESULTS: We found a higher occurrence of three SNPs in patients with platelet hyperaggregability and history of miscarriage (rs1671152, rs1654433, rs1671215). The haplotype analysis showed a significant higher occurrence of two haplotypes (ACGG, CCGT). CONCLUSIONS: Our results support the idea that genetic variability of GP6 regulatory regions can be associated with platelet hyperaggregability - a possible cause of miscarriage.

Platelet Hyperaggregability is Highly Prevalent in Patients With Chronic Kidney Disease: An Underestimated Risk Indicator of Thromboembolic Events.

BACKGROUND: Platelet hyperaggregation is known to be associated with arterial and venous thromboembolic events. The prevalence of platelet hyperaggregation in patients with chronic kidney disease (CKD) has not been described to date. METHODS: Platelet hyperaggregation in patients with renal disease was defined by comparison of platelet aggregation patterns to non-CKD patients without thromboembolic disorders and healthy controls. RESULTS: Among the 30 hemodialysis patients and 34 renal transplant recipients, 20 (67%) and 28 (82%) showed significantly decreased median Δ-epinephrine aggregation and increased 0.5 mol/L epinephrine response (65% and 54%) compared to healthy controls and non-CKD patients. In concordance to the laboratory finding of platelet hyperaggregability, renal transplant recipients showed a high rate of thromboembolic events (normal platelet aggregation: 0 events and platelet hyperaggregation: 30 events in 13 of 28 patients). CONCLUSIONS: Patients with CKD exhibit a hitherto unappreciated high prevalence of platelet hyperaggregability indicating sticky platelet syndrome. Laboratory testing of platelet hyperaggregability may supplement the assessment of thromboembolic complications in patients with CKD.

Frecuencia del síndrome de plaquetas pegajosas en pacientes con pérdidas fetales recurrentes / Frequency of sticky platelet syndrome in patients with recurrent fetal loss

El síndrome de las plaquetas pegajosas es un trastorno plaquetario autosómico dominante considerado como una de las causas más frecuentes de eventos trombóticos. Se cree que el defecto específico puede estar localizado en los receptores de la superficie plaquetaria y está caracterizado por un incremento anormal en la agregabilidad de las plaquetas con difosfato de adenosina, epinefrina, o ambos. En estudios realizados acerca de esta entidad se ha descrito una elevada incidencia, pero esta se ha calculado en pacientes que han tenido episodios trombóticos previos (enfermedad tromboembólica, infarto agudo del miocardio y accidente cerebrovascular), antecedentes familiares o tienen factores de riesgo para este tipo de eventos, mientras que su incidencia en una población de mujeres en edad fértil, con dos o más pérdidas de embarazo y sin antecedentes es desconocida. En el presente trabajo se estudiaron un total de 126 pacientes femeninas con al menos dos pérdidas de embarazo; de ellas, 27 resultaron positivas al estudio de hipersensibilidad plaquetaria con difosfato de adenosina y epinefrina mediante pruebas de agregometría, lo que representa el 21 por ciento de positividad en la población estudiada. Es significativo que la clase de síndrome de plaqueta pegajosa predominante fue de tipo II (hipersensibilidad con epinefrina). Finalmente, destacar que el seguimiento y tratamiento oportuno durante la gestación en las pacientes incluidas en el estudio ha permitido el nacimiento de 4 niños saludables de madres con síndrome de plaquetas pegajosas...

The sticky platelet syndrome is an autosomal dominant platelet disorder considered one of the most frequent causes of thrombotic events. It is supposed that the specific fault can be localized to the platelet surface receptor and is characterized by an abnormal increase in aggregability adenosine diphosphate and/or epinephrine. In studies on this entity a high incidence has been described, but this was calculated in patients who have had previous thrombotic events (thromboembolic disease, myocardial infarction and stroke), family history or risk factors for this kind of events, while its incidence in a population of women of childbearing age with two or more pregnancy losses and no previous history is unknown.During our research a total of 126 female patients with at least two miscarriages were studied; 27 of them showed platelet hypersensitivity to adenosine diphosphate and epinephrine by testing aggregometry, which represents 21 percent positivity in the population studied. It is significant that the sticky platelet syndrome was predominantly of type II (hypersensitivity with epinephrine). In conclusion, we consider important to remark that with the monitoring and opportune treatment during pregnancy, four of the patients included in our study gave birth four healthy children despite the sticky platelet syndrome...

Frecuencia del síndrome de plaquetas pegajosas en pacientes con pérdidas fetales recurrentes / Frequency of sticky platelet syndrome in patients with recurrent fetal loss

El síndrome de las plaquetas pegajosas es un trastorno plaquetario autosómico dominante considerado como una de las causas más frecuentes de eventos trombóticos. Se cree que el defecto específico puede estar localizado en los receptores de la superficie plaquetaria y está caracterizado por un incremento anormal en la agregabilidad de las plaquetas con difosfato de adenosina, epinefrina, o ambos. En estudios realizados acerca de esta entidad se ha descrito una elevada incidencia, pero esta se ha calculado en pacientes que han tenido episodios trombóticos previos (enfermedad tromboembólica, infarto agudo del miocardio y accidente cerebrovascular), antecedentes familiares o tienen factores de riesgo para este tipo de eventos, mientras que su incidencia en una población de mujeres en edad fértil, con dos o más pérdidas de embarazo y sin antecedentes es desconocida. En el presente trabajo se estudiaron un total de 126 pacientes femeninas con al menos dos pérdidas de embarazo; de ellas, 27 resultaron positivas al estudio de hipersensibilidad plaquetaria con difosfato de adenosina y epinefrina mediante pruebas de agregometría, lo que representa el 21 por ciento de positividad en la población estudiada. Es significativo que la clase de síndrome de plaqueta pegajosa predominante fue de tipo II (hipersensibilidad con epinefrina). Finalmente, destacar que el seguimiento y tratamiento oportuno durante la gestación en las pacientes incluidas en el estudio ha permitido el nacimiento de 4 niños saludables de madres con síndrome de plaquetas pegajosas(AU)

The sticky platelet syndrome is an autosomal dominant platelet disorder considered one of the most frequent causes of thrombotic events. It is supposed that the specific fault can be localized to the platelet surface receptor and is characterized by an abnormal increase in aggregability adenosine diphosphate and/or epinephrine. In studies on this entity a high incidence has been described, but this was calculated in patients who have had previous thrombotic events (thromboembolic disease, myocardial infarction and stroke), family history or risk factors for this kind of events, while its incidence in a population of women of childbearing age with two or more pregnancy losses and no previous history is unknown.During our research a total of 126 female patients with at least two miscarriages were studied; 27 of them showed platelet hypersensitivity to adenosine diphosphate and epinephrine by testing aggregometry, which represents 21 percent positivity in the population studied. It is significant that the sticky platelet syndrome was predominantly of type II (hypersensitivity with epinephrine). In conclusion, we consider important to remark that with the monitoring and opportune treatment during pregnancy, four of the patients included in our study gave birth four healthy children despite the sticky platelet syndrome(AU)

Effects of Calcium Channel Blockers and Insulin on the Platelet Function in Patients with Diabetes Mellitus

Platelet aggregability was compared between platelets isolated from normal subjects and patients with diabetes mellitus in order to evaluate the effects of calcium channel blockers and insulin on the platelet function. The threshold aggregating concentration of adenosine diphosphate (ADP), which induces the second phase aggregation and reflects the platelet release reaction, was found to be significantly lower in diabetics than in normal subjects (1.8 microM vs 7.5 microM ). It was observed that the second phase aggregation curve induced by ADP was inhibited by in vitro treatment of platelets with insulin (10-100 microU/ml), verapamil (1-10 microM ), and diltiazem (1 microM) in diabetics. The result also shows that the inhibition was enhanced when insulin and calcium channel blockers were used together for in vitro treatment of diabetic platelets. Thus, the present study suggests that the use of calcium channel blockers combined with insulin would be more effective than the use of insulin alone in the prevention of diabetic vascular disease.