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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).

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are associated with considerable morbidity and mortality, and for as much as twenty-five percent of PE patients the primary clinical appearance is unexpected death. Diagnosis of PE is based on clinical suspicious at first, but sometimes its diagnostics can be extremely difficult. Newly increased interest in an inherited thrombophilic states has been provoked by the discovery of several common inherited abnormalities, i.e. the prothrombin (PT) gene G20210A, Factor V Leiden (FVL) mutation (Arg506Gln), hyperhomocystenemia and homocysteiuria, Wein-Penzing defect, Sticky Platelet Syndrome (SPS), Quebec platelet disorder (QPD) and Sickle Cell Disease (SCD). PE incidence rates increase in recent years. The only explanation at this moment is increased awareness of PE, especially after any kind of surgery, immobile state or unexplained shorthness of breath.

The aim of this study was to evaluate the genetic variability of the selected single nucleotide polymorphisms (SNPs) and examine the association between these SNPs and risk for deep vein thrombosis (DVT) in patients with sticky platelet syndrome (SPS). We examined 84 patients with SPS and history of DVT and 101 healthy individuals. We were interested in 2 SNPs within platelet endothelial aggregation receptor 1 (PEAR1) gene (rs12041331 and rs12566888), 2 SNPs within mkurine retrovirus integration site 1 gene (rs7940646 and rs1874445), 1 SNP within Janus kinase 2 gene (rs2230722), 1 SNP within FCER1G gene (rs3557), 1 SNP within pro-platelet basic protein (rs442155), 4 SNPs within alpha2A adrenergic receptor 2A (ADRA2A; rs1800545, rs4311994, rs11195419, and rs553668), and 1 SNP within sonic hedgehog gene (rs2363910). We identified 2 protective SNPs within PEAR1 gene and 1 risk SNP within ADRA2A gene (PEAR1: rs12041331 and rs12566888; ADRA2A: rs1800545). A haplotype analysis of 4 SNPs within ADRA2A gene identified a risk haplotype aagc ( P = .003). Moreover, we identified 1 protective haplotype within PEAR1 gene (AT, P = .004). Our results support the idea that genetic variability of PEAR1 and ADRA2A genes is associated with platelet hyperaggregability manifested as venous thromboembolism. The study also suggests a possible polygenic type of SPS heredity.

Platelet hyperaggregability, known as sticky platelet syndrome (SPS), is a prothrombotic disorder that has been increasingly associated with pregnancy loss. In this retrospective study, we aimed to investigate the clinical and diagnostic relevance of SPS in 208 patients with infertility and unexplained pregnancy loss history. We studied 208 patients that had been referred to undergo a dose-dependent platelet aggregation response to adenosine diphosphate and epinephrine using light transmission aggregometry modified by Mammen during an 11-year period. Patients&rsquo, platelet aggregation response was compared with platelet function in 29 female healthy controls of fertile age with no previous history of pregnancy loss. We found a prevalence of SPS type II (33.2%) in 208 female patients with infertility and pregnancy loss. ∆-epinephrine-induced platelet aggregation in patients with SPS was significantly decreased (median 7% and range &minus, 21 to 43%) compared to patients without SPS (median 59%, range 7&ndash, 88% and p &lt, 0.0001) and healthy controls (median 57%, range 8&ndash, 106% and p &lt, 0.0001). The optimum SPS-diagnostic cutoff value for ∆-epinephrine aggregation was &le, 32% (sensitivity 95.7%, specificity 95.2%). SPS patients with low-dose acetylsalicylic acid (ASA) therapy (n = 56) showed improved pregnancy outcome (32 pregnancies, live births n = 18 (56%)) compared to SPS patients without low-dose ASA (n = 13) (3 pregnancies, live births n = 1 (33%)). Our study demonstrates the clinical and diagnostic relevance of platelet hyperaggregation in women with infertility and pregnancy loss history. Further studies should investigate the potential of SPS as a novel decisional tool with both diagnostic and clinical implications in infertility and pregnancy loss.

ResumenEl síndrome de plaquetas pegajosas (SPP) es un trastorno que se traduce en una serie de fenómenos protrombóticos a expensas de hiperagregabilidad plaquetaria. Es un trastorno raro y, a pesar de que puede ser identificado eficazmente mediante agregometría plaquetaria, se desconoce la etiología. Algunas publicaciones indican que el 20% de los eventos vaso-oclusivos arteriales corresponden a casos asociados al SPP. El SPP constituye un trastorno inusual; los pocos reportes oscurecen la prevalencia de esta entidad. Tiene implicación en el fracaso de colgajos libres e injertos por la formación de microtrombos. El propósito de este artículo es presentar 2 casos remitidos al Servicio de Cirugía Oral y Maxilofacial Pediátrica. Adicionalmente, se presenta una revisión actualizada sobre la etiología y diagnóstico de esta condición.AbstractSticky platelet syndrome (SPS) is a disorder that is associated with a series of arterial and venous prothrombotic events due to of platelet hyperaggregability. It's a rare condition, and even though there are efficient platelet aggregometry methods to diagnose the disorder, the underlying pathophysiology remains unclear. Some publications suggest that approximately 20% of vaso-occlusive events are of SPS origin. SPS is an unusual condition; the limited number of reports contributes to the lack of documentation regarding this syndrome. SPS is associated with maxillofacial free flap and graft failures due to thrombi formation. The purpose of this article is to present 2 cases of SPS seen in the Pediatric Oral and Maxillofacial Surgery Department together with a review on the etiology and diagnostic features of SPS.

The sticky platelet syndrome (SPS) was described by Mammen in 1983. Since then, scientists in several countries have identified the condition and published cases or series of patients, thus enabling the description of the prevalence of the inherited condition, its salient clinical features, and the treatment of the disease. The diagnosis of the SPS phenotype requires fresh blood samples and special equipment which is not available in all coagulation laboratories. In the era of molecular biology, up to now it has not been possible to define a clear association of the SPS phenotype with a specific molecular marker. Some molecular changes which have been described in platelet proteins in some persons with the phenotype of the SPS are here discussed. Nowadays, the SPS phenotype may be considered as a risk factor for thrombosis and most cases of the SPS developing vaso-occlussive episodes are the result of its coexistence with other thrombosis-prone conditions, some of the inherited and some of them acquired, thus leading to the concept of multifactorial thrombophilia. Ignoring all these evidence-based concepts is inappropriate, same as stating that the SPS is a nonentity simply because not all laboratories are endowed with adequate equipment to support the diagnosis.

Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other conditions have been described so far, which have then allowed to currently detect an inherited or acquired predisposition in approximately 60–70% of patients with thromboembolic disorders. These prothrombotic risk factors mainly include qualitative or quantitative defects of endogenous coagulation factor inhibitors, increased concentration or function of clotting proteins, defects in the fibrinolytic system, impaired platelet function, and hyperhomocysteinemia. In this review article, we aim to provide an overview on epidemiologic, clinic and laboratory aspects of both acquired and inherited rare thrombophilic risk factors, especially including dysfibrinogenemia, heparin cofactor II, thrombomodulin, lipoprotein(a), sticky platelet syndrome, plasminogen activator inhibitor-1 apolipoprotein E, tissue factor pathway inhibitor, paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopenia.

Introduction. Sticky platelet syndrome (SPS) is a prothrombotic disease that is not well recognized and difficult to diagnose. Case Report. We present a case of a 49-year-old diabetic woman on ambulatory peritoneal dialysis therapy who underwent a kidney transplant from living-related donor. The donor was her sister with whom she shared one haplotype and absence of donor specific antibodies. The posttransplant evolution was torpid, developing progressive deterioration, which made us suspect a failure in the graft. Doppler ultrasound reported renal vein thrombosis and hypoperfusion of the renal artery. Without clinical improvement, she required a reintervention that ended in graftectomy, in which the histopathological report showed negative C4d with medullary and cortical infarction. Hematological studies were negative for antibodies against phospholipids, with correct levels of proteins C and S and antithrombin. Platelet aggregometry studies were carried out, which were compatible with SPS. Conclusions. Recognition of SPS in pretransplant studies is difficult if there is no history of previous thrombotic events. However, we must consider this entity in cases of acute thrombosis and loss of the graft of uncertain origin.

Background: Sticky platelet syndrome (SPS) is a common but under-recognized cause of thrombosis. Treatment with antiplatelet drugs results in a low re-thrombosis rate. The aim of this study is to analyze the treatment of persons with SPS in different parts of the world. Methods: Data from 43 publications describing 1,494 patients with SPS worldwide were analyzed. Data concerning treatment was available in 16 of these papers, and involving 332 patients. Results: Three hundred thirty two patients were treated with antiplatelet drugs; 303 were given solely aspirin and 29 received combinations with aspirin (heparin or coumadin), whereas two persons did not receive aspirin. The re-thrombosis rate for patients given antiplatelet drugs was 5/332 (1.5%) and only 3 patients died. Conclusions: Most patients with SPS are treated with antiplatelet drugs worldwide, the re-thrombosis rate is very low. Physicians worldwide are aware of the fact that the best treatment for persons with the SPS is the use of antiplatelet drugs.

Introduction: The sticky platelet syndrome (SPS) is a common cause of thrombosis. There are no prospective studies concerning treatment. Objective: To analyze changes in platelet hyperaggregability of patients with SPS who were given antiplatelet drugs and to assess its association with rethrombosis. Methods: A total of 55 patients with a history of thrombosis and SPS phenotype were prospectively studied before and after treatment with aspirin and/or clopidogrel. Results: Patients were followed for 1 to 129 months, median 13. Of 55 patients, 40 received aspirin, 13 received aspirin + clopidogrel, and 2 received only clopidogrel. The platelet aggregation response to adenosine diphosphate and epinephrine significantly diminished after treatment, and only 2 patients developed rethrombosis 52 and 129 months after starting therapy, with the freedom from rethrombosis rate of the patients being 96.4% at 129 months. Conclusion: Using antiplatelet drugs, the platelet hyperreactivity of patients with the SPS phenotype was reverted; and this translated into a substantial decrease in the rethrombosis rate.

Disequilibrium of hemostasis is central to the pathogenesis of all thromboses, and platelets are essential for primary hemostasis. The platelet membrane glycoprotein receptor is involved in the clot formation in blood; therefore, the changes in related genes could impair platelet aggregation in patients with sticky platelet syndrome (SPS). Patients with SPS who experienced fetal loss were shown to harbor a risk haplotype at GP6 locus. The aim of the study was to examine the genetic linkage of this selected risk haplotype with single nucleotide variations (SNVs) in the coding sequence of the GP6 gene in order to identify possible functional SNVs in association with SPS and fetal loss. A total of 37 patients with SPS manifested fetal loss, and 42 healthy controls were enrolled in the study. The SPS was diagnosed with platelet aggregometry. The SNVs were determined by dideoxy sequencing and high-resolution melting analysis. The missense variations were detected in patients with risk haplotype only. The association analysis showed association of the minor alleles with the SPS manifested by fetal loss as follows—rs1671152 (odds ratio [OR]: 4.667, 95% confidence interval [CI]: 1.462-14.89, P = .006), rs2304167 (OR: 5.085, 95% CI: 1.605-16.10, P = .003), and rs1654416 (OR: 5.085, 95% CI: 1.605-16.10, P = .003). Using the Expectation-Maximization (EM) algorithm, the estimated minor haplotype with predicted protein residue PEAN was significantly associated with the given phenotype (OR: 4.746, 95% CI: 1.486-15.15, P = .005). We have shown that haplotype PEAN associated with SPS and manifested by fetal loss and suggest that the mechanism involved in the action of GPVI has significant effect on GPVI-mediated signal transduction through Syk-phosphorylation.

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 function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in this process. We tested association of 2.5 million SNPs with platelet aggregation responses to three agonists (ADP, epinephrine and collagen) in two cohorts of European ancestry (N

The aim of this study was to detect the prevalence of the polymorphisms of growth arrest—specific gene 6 (Gas6; Gas6 c. 834 + 7G > A) in patients with sticky platelet syndrome (SPS). Sticky platelet syndrome is a hereditary, autosomal dominant thrombophilia characterized by platelet hyperaggregation after low concentrations of platelet inducers—adenosine diphosphate (ADP) and epinephrine (EPI). The cause of SPS still remains unknown, but in recent years it was suggested that Gas6 protein may have a potential role in the pathogenesis of SPS. To assess the Gas6 polymorphisms (Gas6 c. 834 + 7G > A), 128 patients with SPS were included in the study and examined by polymerase chain reaction (PCR) method. GG genotype was detected in 63 (49.2%) patients, GA genotype in 53 (41.4%) patients, and AA genotype in 12 (9.4%) patients. The results in controls did not differ significantly compared to patients with SPS. Our findings did not prove allele A to be less associated with thrombosis and that ‘‘prothrombotic’’ allele G may be associated with higher risk of thrombosis. We cannot support the idea that Gas6 protein and Gas6 polymorphisms may be associated with thrombosis in SPS.

Three-hundred fifty-one women were referred for thrombosis and hemostasis evaluation after suffering recurrent miscarriages. All patients were referred by a high-risk obstetrician or reproductive medicine specialist after anatomic, hormonal or chromosomal defects had been ruled out. These patients were assessed over a three year period. The mean patient age at referral was 34 years and the mean number of miscarriages was 2.9 (2-9). All patients underwent a thorough evaluation for thrombophilia and, when indicated, a hemorrhagic disorder. Of the 351 patients, 29 (8%) had no defect. Of the remaining 322 patients, 7 (2%) had a bleeding disorder: 3 with platelet dysfunction, 1 with Factor XIII deficiency, 3 with von Willebrand’s and 3 with Osler-Weber-Rendu. The remainder of the patients had a thrombophilia as follows: 195 (60%) had antiphospholipid syndrome, 64 (20%) had Sticky Platelet Syndrome, 38 (12%) had MTHFR mutation, 23 (7.1%) had PAI-1 polymorphism, 12 (3.7%) had Protein S deficiency, 12 (3.7%) had Factor V Leiden, 3 (1%), had AT deficiency, 3 (1%) had Heparin-Cofactor II deficiency, 3 (1%) had TPA deficiency, and 6 (2%) had Protein C deficiency. There were a total of 364 defects found in the 312 patients harboring thrombophilia; thus, several harbored two and a few harbored three separate defects. All patients with thrombophilia were treated with preconception ASA at 81 mg/day with the immediate post-conception addition of heparin or LMW heparin (Dalteparin). Both ASA and heparin/LMW heparin were used to term. The first 120 patients were treated with unfractionated heparin at 5,000 U every 24 hours, subcutaneously and the last 192 have been treated with Dalteparin at 5,000 U/day subcutaneously. The patients with MTHFR were also treated with folate at 5 mg/day + pyridoxine at 50 mg/day. All patients were carefully monitored with CBC and platelet counts, anti-Xa levels, frequent ultrasounds and physical exams. Only 2 of the thrombophilia patients suffered another miscarriage; all others had a normal term delivery. There were no pregnancy-related thromboses, no delivery complications and no episodes of post-partum thrombosis. The only bleeding consisted of 1-4 cm bruises at injection sites. No episodes of thrombocytopenia (HIT) were noted. In our experience, thrombophilia is a common cause of recurrent miscarriage and all patients with no anatomical, hormonal or chromosomal defect should be evaluated for thrombophilia or a bleeding disorder. The success rate of normal term delivery in these 312 patients was 94% using ASA + heparin or Dalteparin. In addition, side effects of therapy were minimal.

The sticky platelets syndrome (SPS) is a procoagulant condition based on either arterial, venous, or capillary thrombi caused by hyperesponsive and hyperaggregable platelets. This is a frequent disease, which often remains clinically inapparent, until stressful events or combination with other factors increase the risk of developing SPS. The condition is due to a congenital platelet defect with autosomal dominant characteristics, leading to the increased platelet aggregability when they are challenged with epinephrine and adenosine diphosphate. Nowadays classification of this disorder is based on platelet reactivity to both ADP and epinephrine (SPS type 1), epinephrine alone (SPS type 2), and ADP alone (SPS type 3). The diagnoses of the syndrome depend on the functional aggregometer assay. This condition should be taken into account whenever a patient with thrombophilia is considered.

Over a 36-month period, 46 consecutive Mexican mestizos with a clinical marker associated with a primary hypercoagulable state were prospectively assessed by searching for the sticky platelet syndrome (SPS), the activated protein C resistance (aPCR) phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen activator inhibitor type 1, IgG and IgM isotypes of antiphospholipid antibodies, homocysteine levels, the factor V gene Leiden, Cambridge, Hong Kong, and Liverpool mutations, the 677 C→T mutation in the 5,10-methylenetetrahydrofolatereductase (MTHFR), and the G20210A polymorphism in the 3′-untranslated region of the prothrombin gene. Of the 46 consecutive patients prospectively accrued in the study, only 12 (26%) were males, the median age being 38 years (range 10–63 years). In only four individuals (8%) could we not record any abnormality. In 5/42 patients with abnormal results (12%), a single abnormality was recorded, whereas in the remaining 37, two to five co-existing abnormalities were identified. We found 22 (48%) patients with the SPS, 11 (24%) with the aPCR phenotype, 5 (11%) with the factor V Leiden mutation, 7 (15%) with the prothrombin gene mutation, 29 (63%) with the MTHFR gene mutation, 11 (24%) with the factor V HR2 haplotype, 11 (24%) with antiphospholipid antibodies, 4 (9%) with PS deficiency, 6 (13%) with PC deficiency, one with the FV Hong Kong mutation, and one with AT-III deficiency. The results are consonant with the idea that most cases of thrombophilia in Mexico are multifactorial. Am. J. Hematol. 78:21–26, 2005. © 2004 Wiley-Liss, Inc.

El síndrome de la plaqueta pegajosa es un desorden plaquetario autosómico dominante asociado con eventos tromboembólicos arteriales y venosos. Se caracteriza por hiperagregabilidad plaquetaria en plasma rico en adenosindifosfato y epinefrina. Clínicamente las pacientes pueden presentar angina de pecho, infarto agudo del miocardio, accidentes isquémicos transitorios, accidentes cerebrovasculares, trombosis retiniana, trombosis de arterias periféricas y trombosis venosas, frecuentemente recurrente bajo tratamiento anticoagulante oral. Se presentan cuatro casos de gestantes diagnosticadas y tratadas en la Unidad de Alto Riesgo Obstétrico del Hospital Militar Central, con pruebas diagnósticas para otros eventos hipercoagulables normales que sólo presentaban hiperagregación plaquetaria. Posteriormente se hace una revisión de la literatura.

During an 18-month period, 10 consecutive Mexican mestizos with a clinical marker associated with a primary hypercoagulable state were studied. The assessment of the sticky platelet syndrome (SPS) was done by the method described by Mammen. In addition, the activated protein C resistance phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, plasminogen, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen activator inhibitor type 1, IgG and IgM isotypes of anti-phospholipid antibodies, homocysteine levels, the factor V gene Leiden mutation, the 677 C->T mutation in the 5,10-methylen-tetrahydrofolate-reductase (MTHFR), and the G20210A polymorphism in the 3′-untranslated region of the prothrombin gene were studied. Six patients with the SPS were identified: only one displayed this as the single thrombophilic abnormality; in five others, additional thrombosis-prone conditions were found: heterozygosity for the MTHFR 677 gene mutation in five cases; and, in one case each, heterozygosity for the factor V Leiden mutation, heterozygosity for the factor II G20210A mutation, and antiphospholipid antibodies in another. Four of the six patients had a family history of thrombophilia. All patients were treated with aspirin and no new vasoocclusive episodes have been recorded. SPS in not an infrequent finding in Mexican mestizo thrombophilic patients and may contribute to thrombophilia.

The sticky platelet syndrome (SPS) is a congenital disorder characterized by platelet hyperaggregability to epinephrine and/or adenosine diphosphate; this predisposes affected individuals to acute myocardial infarction, ischemic optic neuropathy, recurrent venous thromboembolism, and transient ischemic cerebral attacks and strokes. Here, we describe an unusual case with recurrent cerebrovascular accidents due to SPS, in the presence of a patent foramen ovale (PFO). We report an unusual case of a 56-year-old female patient with a PFO, who suffered from recurrent strokes despite long-term medication with clopidogrel for SPS. The patient underwent successful transcatheter closure of the PFO, and, in addition, she has been placed on low-dose acetylsalicylic acid. After 18-month follow-up, she demonstrated an intact atrial septum without any vegetations on the percutaneous device until today. She has had no further thromboembolic events. peerReviewed

Sticky platelet syndrome has been described as a hereditary thrombophilic condition. The aim of this study is to identify the presence of platelet hyperaggregability in patients who have experienced thrombosis. Light-transmittance platelet aggregometry was used to assess for spontaneous platelet aggregation, aggregation in response to full and low-dose (LD) epinephrine (Epi) and adenosine diphosphate, as well as arachidonic acid, and identify a distinct pattern of platelet hyperaggregability. Light-transmittance platelet aggregometry results were correlated with PFA-100® (Dade-Behring, Marburg, Germany) results, when available. An exaggerated response to LD Epi was found in 68% of patients with thrombosis compared to only 36% of healthy controls (p = 0.034). Patients with thrombosis, either arterial or venous, demonstrated an exaggerated response to LD Epi nearly twice as frequently as healthy controls, even without significant family history of thrombophilia or other known risk factors for thrombosis. This suggests that platelet hyperaggregability may be multifactorial in nature and not necessarily hereditary.

Although first-time miscarriages are usually caused by chromosomal defects, about 55% of recurrent miscarriages are caused by procoagulant defects that induce thrombosis and infarction of placental vessels. Of recurrent miscarriages, about 7% are caused by chromosome defects, 15% to hormonal de fects, and 10% to 15% to anatomical defects. Recurrent mis carriage involves more than 500,000 women in the United States each year. During the past 4 years, 179 patients, pre- screened for chromosomal, hormonal, and anatomical defects, and found to harbor none, underwent hemostasis defect evalu ation. A total of 160 of these have been analyzed. A hemostasis defect was found in 150 of 160 women ( n = 94% of screened women). The mean age was 33 years; the mean number of miscarriages before referral was three. All women with a pro coagulant defect (149) were treated with preconception ASA at 81 mg/d, and unfractionated porcine heparin at 5000 U every 12 hours was added immediately postconception; both agents were used to term delivery. Only two of 149 patients failed therapy. The defects found were as follows: antiphospholipid syndrome, 67%; sticky platelet syndrome, 21 %; tissue plasmin ogen activator (TPA) deficiency, 9%; factor V Leiden, 7%; high PAI-1, 6%; protein S, 5%; high LP(a), 3%; AT, 2%; protein C, 1%. Thirty-eight patients had more than one defect. In the group with antiphospholipid syndrome, 24% only had a subgroup antibody (antiphosphatidyl-serine, -inositol, -ethanol amine, -choline, -glycerol) or antiphosphatidic acid antibody, in the absence of anticardiolipin antibody or lupus anticoagulant. This finding is similar to that recently reported in early age ischemic stroke patients ( In summary, about 55% of patients with recurrent miscar riage harbor a procoagulant defect to account for placental vascular occlusion. More than 98% will have a normal term delivery with preconception aspirin (ASA) and addition of postconception heparin to term. Patients should be screened by an obstetrician or by reproductive specialists for hormonal and anatomic defects before initiating a procoagulant evaluation; if such prescreening is done, the yield of a defect is high and appropriate therapy leads to an excellent outcome.

The availability of low molecular weight heparin (LMWH), with associated ease of home delivery and enhanced efficacy and safety, has rendered the long-term outpatient use of LMWH feasible. Although warfarin is usually used for long-term secondary prevention, it is not the drug of choice for a variety of conditions such as antiphospholipid thrombosis syndrome, sticky platelet syndrome, and patients with malignancy and other medical conditions who have failed adequate warfarin doses. We assessed the long-term efficacy and safety of outpatient dalteparin in a series of patients with conditions associated with prior warfarin failure or potential to warfarin therapy (antiphospholipid syndrome). The results of this study, detailed herein, demonstrate that long-term dalteparin is highly effective and safe when used as long-term therapy for secondary prevention in selected prothrombotic disorders.

Thrombosis has been attributed to platelet function abnormalities in a variety of vascular diseases. A patient with superior sagittal sinus thrombosis noted to have a normal work- up for hypercoagulable state but who had hyperaggregability of platelets after stimulation with epinephrine is described. A di agnosis of sticky platelet syndrome, type II was eventually made.

Sticky platelet syndrome (SPS) was first described in 1983. However, not until 1995 did the prevalence of SPS receive significant recognition in the medical literature. In 1995 we began to routinely add an SPS evaluation to patients re ferred for assessment for causation of arterial and venous thromboses to a large thrombosis hemostasis referral center. The results of our first 2-year experience suggest SPS to be a common cause of arterial and venous thromboses. With respect to otherwise unexplained venous thrombosis, the prevalence of SPS approximates that of activated protein C resistance (APC- R). During the past 24 months, we have evaluated 153 patients referred for evaluation of unexplained arterial or venous events. An evaluation for common and uncommon blood coagulation protein defects and SPS has been applied to these patients. It has been found that SPS accounted for about 21 % of otherwise unexplained arterial events (acute myocardial infarction, cere brovascular thrombosis, transient cerebral ischemic attacks, retinal thrombosis, and peripheral arterial thrombosis) and ac counted for about 13.2% of otherwise unexplained venous events (deep vein thrombosis, with or without pulmonary em bolus). These findings strongly suggest SPS to be a common cause of arterial and venous thromboses and a workup for SPS should be considered a routine assay in the workup of indi viduals with otherwise unexplained arterial or venous throm botic events. Because treatment with heparin or warfarin will not alleviate the thrombotic tendency of SPS, but simple aspirin therapy almost always will correct the defect and protect the individual from second events, it is particularly important to define the presence of this defect. Key Words: Thrombosis— Platelet defects—DVT—Coronary thrombosis—Cerebral thrombosis—Recurrent miscarriage.

Autosomal dominant hereditary Essential Thrombocythemia (ET) due to the gain of function mutation CG transversion in the splice donor of intron 3 in the TPO gene on chromosome 3q27 in a Dutch and Polish family is associated with marked increased TPO levels and Aspirin-responsive Sticky Platelet Syndrome (SPS). SPS is featured by typical clinical manifestations of aspirin responsive microvascular circulation disturbances including erythromelalgia and atypical transient ischemic attacks. Increase of large platelets in blood smears and large mature megakaryocytes with hyperploid nuclei in a normal cellular bone marrow were diagnostic for autosomal dominant hereditary ET (HET). The spectrum of platelet-mediated thrombophilia in HET is comparable to the aspirin responsive SPS in acquired JAK2 V617F positive ET. The affected members of the Dutch and Polish HET families showed no endogenous erythroid colony (EEC) formation. The first generation of the Dutch HET family, two females and one male had stable increased platelet counts, no features of PV, no splenomegaly during life-long follow-up. Three of four elderly family members in the Dutch HET family developed pancytopenia due to myelofibrosis at the age of 71 and 73 years in two, and evolution in acute myeloid leukemia at age 60 in one. These 3 HET patients were on long-term low dose aspirin to prevent SPS manifestations and not treated cytoreductive agents indicating that evolution of ET into myelofibrosis (MF) and leukemia belong to the natural history of TPO-induced HET. In the congenital HET caused by gain of function mutation in the TPO and the JAK2 gene ( JAK2 V617I and JAK2 R564Q ) the responses of mutated CD33 and CD34+ cells to TPO are increased, but the responses to EPO were normal thereby explaining why HET caused by heterozygous germline TPO and JAK2 mutations are associated with the biological characteristics of ET without PV features.

Thrombotic events are mainly caused by defects in circulating plasma proteins and platelets. Normally, the formers include hereditary clotting defects [e.g. deficiencies in protein-S (PS), in protein-C (PC), in antithrombin (AT) genes, or factor V Leiden, and Prothrombin (PT) G20210A substitution] and autoimmune diseases [(anti-phospholipid-antibodies syndrome (APA)]. Although these conditions are well-described in literature, prothrombotic platelet disorders are less well understood. The sticky platelet syndrome (SPS) is a congenital, autosomal dominant disorder, associated with both arterial and venous thromboembolic events. In pregnant women, complications such as fetal growth retardation and fetal loss have been reported. It is characterized by in vitro platelets hyperaggregability (platelet-rich plasma; PRP) triggered by different agonists responsible for its subclassifcation: adenosine diphosphate (ADP) plus epinephrine (type I), epinephrine alone (type II, the most frequent), or ADP alone (type III). Clinically, patients may present with acute myocardial infarction (AMI), transient cerebral ischemic attacks (TIA), angina pectoris, stroke, peripheral arterial thrombosis, retinal thrombosis, and venous thrombosis (VT) even during oral anticoagulant therapy. Conversely, low-dose aspirin treatment ameliorates the clinical symptoms and normalizes hyperaggregability. Clinical symptoms, especially arterial, often present following emotional stress. Combinations of SPS with other congenital prothrombotic defects have been described. Currently, a precise and definite etiology of this defect is not recognized, but receptors on the platelet surface are considered strongly involved candidates. Normal levels of platelet factor 4 (PF4) and betathromboglobulin (βTG) in plasma suggest that the platelets are not activated at all times; accordingly they appear to become hyperactive upon ADP or adrenaline release. In vivo clumping could temporarily or permanently occlude a vessel, leading to the described clinical manifestations. The syndrome appears to be prominent particularly in patients with unexplained arterial vascular occlusions. Despite studies investigating the role of platelet glycoprotein in SPS have been conducted, the precise defect(s) responsible for the syndrome remains unknown. This review discusses on the SPS and about the main receptors on the platelet surface, including some polymorphisms that appear to be involved in the pathology.

Background: The sticky platelet syndrome (SPS) is an inherited condition which leads into arterial and venous thrombosis. There is scant information about the association between the SPS and obstetric complications. Objective: To assess the relationship of the SPS and fetal loss in a single institution. Material and methods: The obstetric history of all the consecutive female patients prospectively studied along a 324 month period, in a single institution with a history of thrombosis and a clinical marker of primary thrombophilia was reviewed. Results: Between 1989 and 2016, 268 consecutive patients with a clinical marker of primary thrombophilia and a history of arterial or venous thrombosis were studied; of these, 108 were female patients. Within this subset, 77 (71%) had been pregnant at some moment. Twenty eight of these 77 patients (37%) had had an abortion and 24 out of these (86%) were found to have the SPS. On the other hand, in a subset of 73 female patients with the SPS who had been pregnant, 32% had miscarriages (14 had one abortion, 5 two abortions and 4 three or more abortions). These figures are significantly higher than the prevalence of abortions in the Mexican general population of pregnant women, which is 12-13% (chi square = 7.47; p = 0.0063). Accordingly, the relative risk of having a miscarriage is 2.66 times higher in female patients with the SPS than in the general population (p = 0.0014 ). Conclusion: In México, female patients with the SPS experience significantly more miscarriages than the general population. Since the treatment of the SPS is simple and effective and could in turn prevent adverse obstetric outcomes, its investigation in women studied because obstetric complications may be useful and deserves further research. Disclosures No relevant conflicts of interest to declare.

Fetal wastage syndrome is characterized by recurrent spontaneous abortion. Many syndromes are associated with recurrent fetal loss, including anatomical anomalies, endocrine/hormonal abnormalities, and coagulation defects, with coagulation defects accounting for ∼30% of cases. Most procoagulant factor defects are due to inadequate fibrin-mediated implantation of the fertilized ovum into the decidua. However, blood protein/ platelet defects leading to hypercoagulability and thrombosis are associated with thrombosis of placental vessels, precluding viability of the implanted ovum or later fetus. During the past 2 years, we have seen 46 patients with fetal wastage syndrome due to thrombosis-associated hemostasis defects. In this group, there have been three patients with sticky platelet syndrome, one patient with dysfibrinogenemia, four patients with congenital protein S deficiency, 35 patients with anticardiolipin antibodies, and one patient with a lupus anticoagulant. Patients were started on one low-dose aspirin (ASA), 81 mg per day preconception, at time of diagnosis, and low-dose s.c. porcine heparin at 5,000 units every 12 h was added immediately postconception. The combination of low-dose ASA plus low-dose s.c. porcine heparin was used throughout pregnancy. All patients achieving pregnancy have had uneventful, normal deliveries. It appears that blood protein/platelet defects leading to thrombosis and associated with recurrent fetal loss can be successfully managed with the use of preconception low-dose ASA, followed by immediate postconception addition of fixed low-dose porcine heparin, both used throughout pregnancy. Using this regimen, our success rate has been 100%. Ideal heparin doses, which might be much lower than our empirically chosen and currently used doses, remain to be defined in this particular indication. Key Words: Fetal wastage syndrome—Heparin—Aspirin.

We describe a 10-year experience with a con genital platelet abnormality characterized by hyperaggre gability with ADP and/or epinephrine. The syndrome has so far been identified in >200 patients and their families. Clinical symptoms are transient or permanent arterial oc clusions, thrombotic in nature, affecting especially the coronary and cerebral vasculature, including ophthalmic vessels. The patients have no identifiable risk factors and are usually young (5-45 years), and other hypercoagula ble states are excluded. In many cases the vascular acci dent is precipitated by severe stressful events. Occasion ally the syndrome is found in patients with recurrent ve nous thromboembolism while they are on optimal oral anticoagulant therapy. In the laboratory the patients' platelets are hyperaggregable with decreasing ADP and/ or epinephrine concentrations added to platelet-rich plasma. Two forms are identified: Type I is marked by hyperaggregability with ADP and epinephrine, while Type II evidences hyperaggregability only with epineph rine. No abnormalities are found when other aggregation stimulators are used. By electron microscopy the plate lets are more readily activated by surface contact, with a greater tendency toward aggregate formation. Plasma lev els of platelet release proteins, platelet factor 4, and β-thromboglobulin are not elevated. The syndrome is treated with low-dose aspirin, which reverses the hyper aggregability and improves clinical symptoms. We hy pothesize that in vivo adrenaline release leads to in creased platelet clumping, which can transiently or per manently occlude small vessels. It is conceivable that altered surface receptors on the platelets might be respon sible for this congenital problem.