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Sticky platelet syndrome (SPS) is a prothrombotic thrombocytopathy with familial occurrence, characterized by hyperaggregability of platelets in response to adenosine diphosphate (ADP), epinephrine (EPI) or both. The syndrome has been identified in approximately 21% of unexplained arterial thrombotic episodes, regarded to be the most common thrombophilia in arterial thrombosis and 13.2% of unexplained venous thromboembolism (VTE). The relatively young age at the first manifestation, relation to fertility and pregnancy, seriousness of the symptoms, easy and effective management of the disorder indicate to the necessity to take it into account in the differential diagnosis of the underlying cause of the thrombotic event. As the various localizations of the thrombosis in SPS have been reported, its management often requires a multidisciplinary approach. This review deals with the clinical aspects of thrombophilia, its etiopathogenesis, diagnosis as well as novel advances in the treatment and outlines the challenges for the further research.

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 cau...

HISTORY AND ADMISSION FINDINGS A 40-year-old woman was admitted to the emergency room because of severe angina pectoris and dyspnoe at rest. She developed ventricular fibrillation a few minutes later from which she had to be resuscitated . After intubation and controlled ventilation immediate angiocardiography was performed while she was still in cardiogenic shock. Coronary angiography ten days before had been unremarkable. DIAGNOSTIC FINDINGS AND THERAPY The second coronary angiogram revealed severe thrombotic lesion at the origin of the left anterior descending branch (LAD) and total occlusions of the peripheral LAD and of the first marginal branch. After intracoronary application of 10 mg abciximab and coronary stent implantation in the origin of the LAD the patient had good clinical improvement. Massive pulmonary embolism two days later, despite of effective heparinization and inhibition of platelet aggregation (as measured by partial thromboplastin time), was treated successfully by regional injection of 100 mg tissue plasminogen activator (t-PA). Tests for possible hypercoagulability showed no detectable changes in the clotting and fibrinolytic system with a normal platelet count. In a standardized aggregation test of platelets hyperaggregation in response to ADP and epinephrine, also at low test doses, revealed the presence of a sticky platelet syndrome. CONCLUSION This case history suggests that enhanced platelet aggregation associated with sticky platelet syndrome may provoke myocardial infarction even in angiographically normal coronary arteries.

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.

Platelets play an important role in hemostasis, thrombosis, and atherosclerosis. Most of our understanding of platelets is based on their function in hemostasis, as it relates to quantitative and qualitative bleeding disorders. In hemostasis, platelets perform two major functions. First, because of their ability to adhere and aggregate at sites of endothelial injury, they facilitate the initial arrest of bleeding, also called primary hemostasis. Second, on ‘‘activation’’ at the site of vessel injury, they provide the surfaces onto which the factors of the coagulation system can be bound, thus keeping clot formation localized. The physiology and biochemistry of platelets has been the subject of extensive reviews [1–4] and will not be discussed in this context. Although the pathophysiology of the role of platelets in bleeding disorders is reasonably well understood, less is known about the involvement of platelets in thrombosis and atherosclerosis, though more patients have the latter than have bleeding problems. ‘‘Discovery of such abnormalities is the challenge of the future in platelet research’’ [2]. The role of platelets in the pathogenesis of arterial thrombosis in particular is relatively well known. Most arterial thrombotic events reside in clot formation at sites of atherosclerotic lesions, though other vascular diseases can also be involved. Ruptures at the base of the atherosclerotic plaques appear to precipitate thrombus formation [5,6]. As in normal hemostasis, platelets will adhere to exposed collagen fibers, aggregate, and initiate, together with tissue factor (TF), the activation of the coagulation system [7]. This leads to thrombus formation with temporary or permanent vascular occlusion. Atherosclerosis is the most prevalent reason for the development of acute myocardial infarction (AMI)

The role of platelet hyperaggregability as a possible risk factor for venous thromboembolism is not well defined. Some authors described enhanced maximal platelet aggregation in platelet aggregometry as a contributing factor for arterial and venous thrombosis. This syndrome has been termed “sticky-platelet syndrome” (SPS). The diagnosis of SPS is based on the demonstration of platelet hyperaggregability in aggregometry after stimulation with epinephrine (EPI) and/or adenosine diphosphate (ADP). We investigated platelet hyperaggregability in platelet-rich plasma (PRP) of patients (n=34) with unexplained venous thromboembolism in comparison to healthy individuals (n=53). For analysis, platelet aggregometry was performed and the influence of epinephrine, adenosine diphosphate, collagen (Coll) and thrombin receptor-activated peptide (TRAP-6) as agonist were determined. Compared to the control group, patients with venous thromboembolism showed an enhanced maximal platelet aggregation with low concentrations of TRAP-6 (2 μM) and collagen (0.05 μM). In contrast, we could not detect an increased platelet aggregation with EPI or ADP. Our results indicate that platelet hyperaggregability may represent an independent risk factor in patients with otherwise unexplained venous thromboembolism. In our study, low concentrations of TRAP-6 and collagen are superior to EPI and ADP to define platelet hyperreactivity in platelet aggregometry.

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

PURPOSE The purpose of this study was to report unusual findings from a hypercoagu-lability workup of a patient with a retinal vein occlusion and to suggest the importance of investigating hypercoagulability in patients with similar presentations. METHODS This is a retrospective case report of a patient seen in the clinic during a several-month period. RESULTS The laboratory evaluation of the patient showed decreased antithrombin III activity and a prothrombin mutation, and platelet evaluation was consistent with sticky platelet syndrome. CONCLUSION It is important to take a detailed history and pursue the possibility of hypercoagulability as an etiology for retinal vein occlusion in patients outside the classic, younger age group. This can lead to prompt intervention and possible prevention of future thrombotic events.

The sticky platelet syndrome is a congenital disorder, characterized by abnormal platelet aggregation in response to epinephrine and/or adenosine phosphate. We present a case of intraoperative carotid artery thrombosis, after patch angioplasty. The successful repair was only feasible on administration of antiplatelet therapy. Presence of sticky platelet syndrome should be considered during vascular operative interventions, and load of antiplatelet agents should be given in patients with unexplained repeated thrombosis of arterial repair, as we described and reported this case.

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.

We report a case of a patient who developed clinical symptoms of sticky platelet syndrome (SPS) during free microvascular flap transplantation, following resection of an oral tumor. Multiple arterial thromboses of two free tissue transfers occurred as a probable result of SPS. Diagnosis and treatment of the various forms of SPS are described.

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.

The treatment of hereditary and acquired thrombophilic disorders is based on an understanding of the disease pathophysiology, prevalence, associated morbidity and mortality, and available therapeutic options. Genetic mutations are identified that result in activated protein C (APC) resistance and hyperhomocyst(e)inemia. The underlying etiologies are less well-defined; however, the disorders of factor XII deficiency, dysfibrinogenemia, Wien-Penzing platelet defect, and sticky platelet syndrome (SPS) are treatable inherited thrombophilias. Antithrombin deficiency, protein C and protein S deficiencies, and plasminogen deficiency are disorders both inherited and acquired. Antiphospholipid antibodies, myeloproliferative syndromes, and Trousseau's syndrome are acquired. Treatment for acute arterial thrombosis or venous thromboembolism is the same or similar for all thrombophilic disorders. Long-term management is based on the risk of a primary or recurrent acute thrombotic event, compared with the risk of the proposed therapy. Few blinded, controlled studies are available to validate treatment recommendations. When long-term anticoagulation is advised, careful consideration should be given to the risk associated with therapy. Bleeding risk, variable efficacy, and the risk of cutaneous necrosis limit the use of warfarin. Fixed low-dose unfractionated porcine heparin and low-molecular-weight heparins (LMWH) offer significant advantages for long-term management. These recommendations are derived from an analysis of the pertinent medical literature and are expected to change with the progress of clinical and laboratory investigation.

The human hemostatic system consists of multiple independent, yet integrally related, cellular and protein components that function to maintain blood fluidity under normal conditions and promote localized, temporary thrombus formation at sites of vascular injury. A normal hemostatic system is the human physiologic defense against exanguination. An abnormal hemostatic system can result in pathologic bleeding, vascular thrombosis, or both. The hemostatic system comprises of six major components: platelets, vascular endothelium, procoagulant plasma protein factors, natural anticoagulant proteins, fibrinolytic proteins, and antifibrinolytic proteins. Each of these six hemostatic components must be present in a fully functional form and in an adequate quantity to prevent excessive blood loss following vascular trauma and at the same time prevent pathologic thrombosis. The hemostatic system is highly regulated and maintains a delicate balance between a prohemorrhagic state and a prothrombotic state. Any significant acquired or congenital imbalance in the hemostatic scales can lead to a pathologic outcome. Alterations in the quantitative and qualatative status of any hemostatic cellular or protein element can have significant biologic effect. Platelet deficiency (thrombocytopenia), platelet adhesion defects, and platelet aggregation disorders are associated with an inability to form an adequate primary hemostatic platelet plug and can lead to significant mucocutaneous bleeding and post-traumatic, life-threatening hemorrhage. In contrast, a marked increase in platelet count (thrombocytosis) and accentuated platelet aggregation (sticky platelet syndrome) are associated with thromboembolic events. 32 Deficiency of a procoagulant factor integral to the intrinsic (factors XI, IX, and VIII), extrinsic (factor VII), or common (factors X, V, II and fibrinogen) pathway of coagulation is associated typically with a variable degree of bleeding tendency. Elevated levels of procoagulant factors, such as factor VIII, fibrinogen, and factor VII, however, are recognized risk factors for vascular disease. 28,47 Deficiency of natural anticoagulant proteins, such as protein C, protein S, antithrombin III (AT-III), and heparin cofactor II (HC-II), is associated with venous thromboembolic disease; a natural anticoagulant protein excess state associated with bleeding has not been described to date. 13 Deficiency of a fibrinolytic cascade component, such as tissue-type plasminogen activator (t-PA) or plasminogen; and excess plasma levels of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), have been linked to hypercoagulability and thrombosis. 24,29,53 Deficiency of fibrinolytic inhibitors, such as α-2 antiplasmin and PAI-1, may precipitate a hyperfibrinolytic bleeding state. 30,52 Deficiency of endothelial cell-derived von Willebrand factor is associated with altered primary and secondary hemostasis caused by deficient platelet anchoring at sites of vascular injury and shortened factor VIII survival characteristic of von Willebrand's disease. 20 Deficient endothelial cell production of thrombomodulin or release of t-PA may be associated with a thrombotic tendency. 19 The balance between these opposing groups of proteins and not the level of any individual factor seems most critical to hemostatic regulation. Pregnant women differ from nonpregnant adults in many physiologic and biochemical aspects. Normal pregnancy is associated with major changes in the coagulation and fibrinolytic systems. The many hemostatic derrangements detected during pregnancy must be considered to represent physiologic, adaptive, and preparatory mechanisms for the hemostatic challenges of delivery rather than pathologic processes. Most pregnant women do not manifest overt bleeding nor thrombotic problems. The hemostatic changes observed in each trimester of normal pregnancy and the puerperium reflect diverse changes in coagulation factor, fibrinolytic protein, regulatory protein, and cellular component activation, release, consumption, and synthesis. The fact that most hemostatic factors and proteins are liver derived, makes a review of coagulation alterations in pregnancy an appropriate component of an article on the liver and pregnancy. This article focuses on all hemostatic components involved in primary hemostasis (platelet plug formation) and secondary hemostasis (fibrin mesh formation) as well as the mechanisms responsible for thrombus localization (natural anticoagulants) and ultimate removal (fibrinolytic cascade proteins). The effects of each trimester of normal pregnancy and the puerperium on each of the major components of the hemostatic system are examined. Particular attention is paid to the balance between procoagulant and anticoagulant mechanisms and the net effect of the hemostatic changes at different periods during pregnancy.

Background: Coagulation disorders are common in young adults (age less than 55 years) with ischemic stroke. Objectives: To describe a young woman with bilateral strokes of undetermined etiology who had three significant hemostatic disturbances. These were protein S deficiency, Factor V Leiden heterozygosity, and sticky platelet syndrome. The Factor V Leiden mutation was also present in one of her children. Conclusions: Young patients with cryptogenic stroke warrant a thorough evaluation for hypercoagulable states. More than one coagulation disorder can coexist in the same patient and the spectrum of hemostatic abnormalities may influence the patient’s treatment and may have implications for screening of other family members.

We report a young patient who presented with nonarteritic anterior ischaemic optic neuropathy associated with the sticky platelet syndrome (SPS, a congenital prothrombotic disorder). A 15-year-old boy presented with a sudden, painless onset of a right inferior altitudinal visual field defect and marked optic disc oedema. Cranial magnetic resonance imaging (including orbits), orbital ultrasound and haematological investigations including a routine hypercoagulability work-up were negative. Further evaluation showed a positive assay for SPS which was confirmed on repeat testing. The SPS (characterized by platelet hyperaggregability and vascular occlusion) may be a potential thrombophilic risk factor for nonarteritic anterior ischaemic optic neuropathy.

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.

Background: The relationship between activated protein C resistance (APCR) and arterial stroke is uncertain. It has been speculated that multiple inherited or acquired prothrombotic conditions may alter the hemostatic balance towards thrombotic events. Methods: Case series from a University medical center. Results: In a series of 28 Caucasian patients under age 55 with cerebral ischemic events, nine were found to have activated protein C resistance. Five of nine patients (56%) had additional hematologic abnormalities. Four patients had elevated anticardiolipin IgG antibodies. Other abnormalities identified included Type I protein S deficiency, sticky platelet syndrome, and a positive lupus anticoagulant. Conclusions: Activated protein C resistance is relatively common in young adults with cerebral ischemic events and may be accompanied by other hematologic abnormalities. The constellation of hemostatic abnormalities may impact the type of and intensity of the antithrombotic regimen. There are also implications for family members of affected patients. Finding evidence of APCR should not preclude a complete hemostatic evaluation in the young stroke patient.

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.

A 64-year-old male patient presented with painful ulcerations and livedo racemosa of both lower limbs. He had a history of cerebral and myocardial infarctions. Dermatohistologic findings and laboratory tests of the patient's coagulation system revealed the diagnosis of livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome type II. Systemic treatment with acetylsalicylic acid and heparin as well as topical therapy with disinfectant and granulation-inducing agents resulted in improvement of the skin lesions.

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.

The aim of the study was to evaluate the genetic variability of the GP6 gene in patients with sticky platelet syndrome (SPS), a disorder characterized by platelet hyperaggregability, and thus to identify the genetic changes of the glycoprotein VI with possible relation to the platelet hyperaggregability.Seventy-one patients with SPS, clinically manifested as ischemic stroke, and 77 controls without SPS and with negative personal history of thromboembolic events were involved. SPS was diagnosed by platelet aggregometry (PACKS-4 aggregometer, Helena Laboratories) according to the method and criteria described by Mammen and Bick. Seven single-nucleotide polymorphisms (SNPs) of the GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs1613662, rs12610286, and rs1654431) were evaluated with the use of restriction-fragment-length polymorphism analysis.All allele and genotype frequencies were comparable between both SPS patients and the control group with no statistically significant differences. The haplotype analysis showed a higher occurrence of the one major haplotype (TTGTGA, 0.228 vs. 0.174; odds ratio (OR) 1.421; confidence interval (CI) 0.799-2.526) and two minor haplotypes (CGATAA, 0,026 vs. 0,006; OR 4.117; CI 0.443-38.25; TTGTGG, 0.018 vs. 0.009; OR 2.107; CI 0.259-17.12) in patients with SPS. None of haplotype differences was statistically significant. However, both the allele G of SNP rs12610286 (P = 0.029; OR 2.411; CI 1.134-5.123) and one major haplotype (TTGTGA; P = 0.012; OR 2.749; CI 1.223-6.174) were found significantly more frequent in patients with SPS type I in comparison with controls.Our results, especially higher occurrence of four haplotypes in SPS patients, can support an idea that variability of the GP6 gene may be associated with the platelet hyperaggregability in SPS.

The GP6 gene encodes the GPVI, a crucial platelet membrane glycoprotein, for adequate platelet activation, adhesion and aggregation. The objectives of the present study were to assess the genetic variability of the GP6 gene in patients with platelet hyperaggregability phenotype, known as sticky platelet syndrome (SPS) manifesting as deep vein thrombosis (DVT), and/or pulmonary embolism, and in controls; and to evaluate its role in the pathogenesis of venous thromboembolism (VTE) in SPS. Seventy-seven patients with SPS and 77 healthy blood donors as controls were enrolled. Light transmission aggregometry was used to diagnose SPS according to the method of Mammen and Bick. Seven single-nucleotide polymorphisms (SNPs) of the GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs12610286, rs1654431, rs1613662) were assessed using restriction fragment length polymorphism analysis. A significant association between 1613662-G [P < 0.05, odds ratio (OR) 2.087, confidence interval (CI) 1.049-4.148], 1654419-A (P < 0.05, OR 2.161, CI 1.020-4.577) and VTE was found in patients with SPS. The analysis based on SPS type revealed a significantly higher occurrence of 1671153-G (P < 0.05, OR 2.317, CI 1.103-4.865) and 1654419-A (P < 0.05, OR 2.317, CI 1.103-4.865) in the SPS type II compared to the control group. No association between the studied GP6 genotypes and the severity of VTE (pulmonary embolism vs. DVT) was found. In the patients, significant positive relationship between the 1671153-G, 1654419-A, 1613662-G alleles and male sex was observed. GP6 SNPs 1613662-G, 1671153-G and 1654419-A alleles are associated with an increased risk of VTE in SPS. They could contribute to the SPS phenotype.

Introduction: The sticky platelet syndrome (SPS) seems to be a common cause of thrombosis, although no molecular substrate to explain platelet hyperaggregability has been found. Objective: To analyze an association between the SPS phenotype and the platelet glycoprotein (GP) IIIa PLA1/A2 (human platelet antigen [HPA]-1a/b) gene polymorphism. Methods: Along an 18-month period, Mexican mestizo thrombophilic patients were prospectively accrued. The SPS phenotype was assessed by aggregometry, whereas a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction analysis was used to detect the PLA1 and PLA2 alleles. Results: A total of 95 individuals with SPS and 127 healthy donors were studied; in 11 of the donors and 16 of the patients with SPS the A2 allele of the GP IIb/IIIA was found, yielding a weak and nonsignificant association (odds ratio 2.14, 95% CI 0.94-4.85). Conclusion: In Mexican mestizo patients, the platelet GP IIIa PLA1/A2 gene polymorphism does not lead to the SPS phenotype.

Introduction: Sticky platelet syndrome (SPS) is most likely a hereditary thrombophilia characterized by platelet hyperaggregation after low concentrations of platelet inducers—adenosine diphosphate and/or epinephrine. We present 9 kindreds with SPS familial occurrence. Material and Methods: Familial trait of SPS was looked up in the database of the National Center of Hemostasis and Thrombosis. Families with at least 3 SPS-positive members were studied, described, and presented. Results: In the group of 1093 symptomatic patients, SPS was confirmed in 240 cases. Familial occurrence with at least 3 SPS-positive relatives was found in 9 cases. Conclusion: The exact pathogenesis of SPS is not sufficiently explained. Our findings seem to support the idea that SPS might have an autosomal dominant hereditary fashion.

Objective: Sticky platelet syndrome (SPS) is a common autosomal dominant inherited platelet disorder. SPS is characterized by platelet hyperreactivity and is associated with arterial and venous thrombosis. The aim of this study was to determine the role of SPS in patients with uninduced venous thrombosis. Material and Methods: The study included 28 patients (15 male and 13 female) with uninduced venous thrombosis. SPS was defined according to Mammen’s aggregation method, which is described in detail elsewhere. Results: According to the defined ranges for platelet hyperreactivity, 3 (50%) patients, 2 (33%), and 1 (17%) (n =6 [21%]) with a confirmed diagnosis were classified as type II, I, and III SPS, respectively. In 1 patient SPS was the only hereditary abnormality noted. The other 5 patients carried other inherited coagulation defects, in addition to SPS. Conclusion: The present findings indicate that the prevalence of SPS was 21% in the patients with uninduced venous thrombosis. We therefore suggest that SPS should be considered in the differential diagnosis of such cases. Conflict of interest:None declared.

BACKGROUND: Sticky platelet syndrome is an autosomal-dominant thrombophilia characterized by platelet hyperaggregability in the presence of adenosine diphosphate or epinephrine. The result clinically can be widespread thromboses, often arterial, in patients without apparent risk factors for thrombotic disease. Limited data exist regarding its role in adverse pregnancy outcomes. CASE: A gravid woman with two previous first-trimester miscarriages presented at 11 weeks of gestation with a deep venous thrombosis. Despite anticoagulation, she developed extensive and progressive arterial and venous thromboses and suffered a fetal demise. A thrombophilia panel was unremarkable, but platelet aggregometry demonstrated hyperactive platelets in the presence of adenosine diphosphate and epinephrine consistent with sticky platelet syndrome. CONCLUSION: Sticky platelet syndrome causes arterial thromboses and may be an underappreciated etiology for adverse pregnancy outcomes.

Sticky platelet syndrome (SPS) leads to hyperaggregabilty of platelets in response to physiologic stimuli. In this report we describe three patients with clinical symptoms of SPS after renal transplantation. The first patient developed an infarction of her transplant kidney with additional, subsequent renal microinfarctions. The second patient suffered multiple strokes and deep vein thrombosis with episodes of pulmonary embolism and ischemic bowel disease due to colonic microinfarctions. The third patient experienced a long episode of unexplained respiratory and graft dysfunction immediately after transplantation until therapy for SPS was initiated, at which point symptoms resolved quickly. Kidney transplant recipients with SPS may be at increased risk of developing thrombosis, given that most immunosuppressive drugs are known to induce either endothelial cell damage or augment platelet aggregation. All patients awaiting renal transplantation should be screened for a history of thrombosis and, if appropriate, tested for SPS. Affected patients should receive dose-adjusted acetylsalicylic acid.

These defects are not as common as factor V Leiden, but they are more common than many other hereditary procoagulant defects. The incidence of the prothrombin gene (G20210A) mutation is not yet known with certainty, but it may approach or even exceed that of factor V Leiden. These defects also seem less common than hereditary sticky platelet syndrome; however, they are all common enough that they always should be considered in any individual with unexplained thrombosis and should be part of the work-up for patients with thrombotic disorders. Of the defects discussed herein, prothrombin G20210A mutation seems, thus far, to be more common than AT, protein C, protein S, or HC-II defects. Assessment of prothrombin gene mutation should be part of the primary evaluation of patients with unexplained thrombosis.

The sticky platelet syndrome (SPS) is an autosomal dominant platelet disorder associated with arterial and venous thromboembolic events. It is characterized by hyperaggregability of platelets in platelet-rich plasma with adenosine diphosphate (ADP) and epinephrine (type I), epinephrine alone (type II), or ADP alone (type III). Clinically, patients may present with angina pectoris, acute myocardial infarction (MI), transient cerebral ischemic attacks, stroke, retinal thrombosis, peripheral arterial thrombosis, and venous thrombosis, frequently recurrent under oral anticoagulant therapy. Clinical symptoms, especially arterial, often present following emotional stress. Combinations of SPS with other congenital thrombophilic defects have been described. Low-dose aspirin treatment (80 to 100 mg) ameliorates the clinical symptoms and normalizes hyperaggregability. The precise etiology of this defect is at present not known, but receptors on the platelet surface may be involved. Normal levels of platelet factor 4 (PF4) and beta-thromboglobulin in plasma suggest that the platelets are not activated at all times; 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 especially in patients with unexplained arterial vascular occlusions.

A 40-year-old man noticed blurred vision in his right eye which lasted 2 days and then improved. Four days later, he had central blurring of vision in his left eye which was noticed upon awakening. This progressed throughout the day until only a small temporal island of vision remained. He had a previous episode of left-sided numbness, weakness and headache 3 months prior, all of which resolved spontaneously. He was referred to the Neuro-Ophthalmology Clinic. Past medical and surgical history was unremarkable. …

Increased platelet aggregation induced by adenosine diphosphate and epinephrine and enhanced platelet activation response to surface contact are the key features of the “sticky platelet syndrome”, in which the phenotype is transmitted with an autosomal dominant pattern. Two thirds of the patients with this syndrome have a positive family history of thrombo-embolic disease, which may be triggered by stress. We have seen two patients suffering from intracranial arterial and venous sinus thrombosis due to sticky platelet syndrome. Hyperaggregability of the platelets after stimulation with adenosine diphosphate and epinephrine was found in both. Case 1: A 43 year old man with a superior sagittal and right transverse venous sinus thrombosis developed subdural hygromas and a venous infarct of the parietal lobe. After burr hole evacuation of the hygromas, aspirin and phenoprocumone were prescribed. The patient made a good neurological recovery. Case 2: A 52 year old woman experienced spontaneous occlusion of a right MCA branch. The work-up revealed bilateral MCA and a basilar tip aneurysm. During the attempt to treat the basilar tip aneurysm by endovascular means, a thrombus formed within the left vertebral artery and was dislodged to both posterior cerebral arteries (PCAs). Local intra-arterial fibrinolysis yielded good recanalization of both PCAs. No new neurological deficit occurred. Continuous prophylaxis with aspirin was started. In sticky platelet syndrome stress and adrenaline release can trigger the thrombosis of intracranial arterial or venous vessels in otherwise healthy subjects. This is a potential cause of thromboembolic complications during endovascular procedures. Low-dose aspirin normalizes platelet hyperaggregability.