Juraj Sokol

Platelet aggregation abnormalities in patients with fetal losses: the GP6 gene polymorphism.

OBJECTIVE To evaluate the GP6 gene polymorphism in patients with sticky platelet syndrome (SPS) and fetal loss. DESIGN Genetic association study. SETTING Perinatal center. PATIENT(S) Twenty-seven patients with SPS, manifested as fetal loss, and 42 control subjects without SPS and no history of fetal loss and thrombosis. INTERVENTION(S) SPS was diagnosed by platelet aggregometry (PACKS-4 aggregometer; Helena Laboratories). Seven single-nucleotide polymorphisms (SNPs) of the GP6 gene were evaluated. MAIN OUTCOME MEASURE(S) Occurrence of SNPs of the GP6 gene in SPS patients versus control subjects. RESULT(S) We found a higher occurrence of three SNPs of the GP6 gene in SPS patients versus control subjects (rs1671153: 0.204 vs. 0.048, odds ratio [OR] 5.116, 95% confidence interval [CI] 1.536-17.03; rs1654419: 0.204 vs. 0.071, OR 3.326, 95% CI 1.149-9.619; rs1613662: 0.204 vs. 0.071, OR 3.326, 95% CI 1.149-9.619). The haplotype analysis showed a significantly higher occurrence of two haplotypes (CTGAG in haplotype 5: 0.185 vs. 0.059, OR 3.568, 95% CI 1.142-11.14; and CGATAG in haplotype 6: 0.204 vs. 0.048, OR 4.961, 95% CI 1.488-16.53). CONCLUSION(S) Our results, especially the higher occurrence of haplotypes CTGAG and CGATAG in SPS patients, support the idea that GP6 gene polymorphism may be associated with platelet hyperaggregability, a possible cause of fetal loss.

Different models of inheritance in selected genes in patients with sticky platelet syndrome and fetal loss.

INTRODUCTION The aim of this study was to evaluate the genetic variability of selected single nucleotide polymorphisms (SNPs) within GAS6 and PEAR1 genes and explore the association between selected SNPs and risk for fetal loss in women with sticky platelet syndrome (SPS). MATERIALS AND METHODS We examined 23 female patients with SPS and history of spontaneous abortion, and 42 healthy women who served as controls. The diagnosis of SPS was established by light transmission aggregometry according to methods and criteria developed by Mammen et al. We also assessed four SNPs within the GAS6 gene (rs7400002, rs1803628, rs8191974, rs9550270) and two SNPs within PEAR1 gene (rs12041331, rs12566888). RESULTS We identified two SNPs within PEAR1 gene (rs12041331, rs12566888) and one SNP within GAS6 gene (rs9550270) that have higher occurrence in SPS patients with history of abortion. An increased risk for abortion was observed in carriers of the rs7400002 within GAS6 gene. Conversely, we found that the T allele of PEAR1 c. -9-4663G > T polymorphism appears to be protective for fetal loss. CONCLUSION Our results support the idea that genetic variability of GAS6 and PEAR1 genes may be associated with platelet hyperaggregability. The study also suggests a possible polygenic type of SPS heredity.

Nine Kindreds of Familial Sticky Platelet Syndrome 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.

Sticky platelets syndrome in a young patient with massive pulmonary embolism.

Patient: Female, 51 Final Diagnosis: Sticky platelets syndrome Symptoms: Pulmonary embolism Medication: — Clinical Procedure: Thrombolysis Specialty: Hematology Objective: Disease of unknown ethiology Background: Sticky platelets syndrome (SPS) is an inherited thrombophilia characterized by platelet hyperaggregability, which can lead to the higher risk of thrombosis. The etiology of SPS remains unclear, but several gene polymorphisms have been recently studied and autosomal dominant heredity is suspected. Although SPS is traditionally connected with arterial thrombosis, several cases of SPS as a cause of venous thromboembolism have been described. Case Report: We report the case of a 51-year-old apparently healthy woman with massive pulmonary embolism, who required thrombolytic therapy. In this patient SPS was identified as the only condition leading to higher risk of developing thromboembolic disease. Conclusions: Although at present few physicians have practical experience with SPS, this syndrome may lead to serious health problems or even death. The presented case points to the benefit of SPS diagnostics in standard screening of inherited thrombophilia for effective prophylaxis and treatment in patients with venous thromboembolism.

Progress in the Understanding of Sticky Platelet Syndrome.

&NA; The knowledge on the etiology of thrombosis has increased tremendously over the past decades. Nevertheless, Virchow triad is still traditionally invoked to explain mechanisms leading to thrombosis, alleging concerted roles for abnormalities in blood composition, vessel wall components, and blood flow in the development of arterial and venous thrombosis. Recent decades have been focused primarily on describing abnormalities in blood composition, including defects of coagulation proteins and platelets. Although defects of coagulation factors are relatively well‐described in the literature, prothrombotic platelet disorders are still less understood. One such defect, the Wien‐Penzing defect was first described in 1991. Another platelet defect is sticky platelet syndrome (SPS). In this article, we review information about SPS, and we propose a new definition and standardization of diagnostic criteria. We also attempt to explain the causes and consequences of this condition.

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

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

Thrombin Receptor Agonist Peptide–Induced Platelet Aggregation Is Reduced in Patients Receiving Dabigatran

The availability of direct oral anticoagulants has caused a paradigm shift in thrombosis management. The direct thrombin inhibitor dabigatran seems to obstruct tenase complex by inhibiting thrombin generated in the initial phase and feed back to the amplification phase of cell-based coagulation reactions. However, it is still not fully understood if and how dabigatran impact platelet function. This observational study aimed to assess in vitro platelet function in patients with atrial fibrillation receiving dabigatran. Platelet aggregability was tested with platelet-rich plasma using platelet aggregometry (PACKS-4 aggregometer). Blood samples were stimulated with thrombin receptor agonist peptide (TRAP; 32 μmol/L). Results: A total of 28 patients with nonvalvular atrial fibrillation were enrolled. The mean age was 71.57 (9.75) years (range: 50-87 years), 16 patients were women, and the mean CHA2DS2VASc score was 3.93 (1.41). All patients began treatment with dabigatran as initial anticoagulant treatment. The minimum term use of dabigatran was 18 days. Dabigatran doses were 110 mg (57.14%) or 150 mg (42.86%) twice daily. The TRAP-induced platelet aggregation was significantly lower 2 hours after taking dabigatran compared to baseline value (79.39 [13.38] vs 90.14 [10.5]). Conclusion: The TRAP-induced platelet aggregation was reduced in cardiovascular patients 2 hours after receiving dabigatran. Our findings could have some important clinical implications because platelet aggregation and coagulation cascade are affected at the same time.

Fibrinogen Martin: A Novel Mutation in FGB (Gln180Stop) Causing Congenital Afibrinogenemia

We readwith great interest the topical article by deMoerloose et al1 in Seminars in Thrombosis and Hemostasis regarding congenital afibrinogenemia. Accordingly, we recently corresponded anovelmutation in an afibrinogenemicpatientwith a proposed new pathological molecular mechanism underlying afibrinogenemia.2Wehave named this novelmutation “fibrinogenMartin”, and nowwish to expand our intial report to also describefindingswith thehypofibrinogenemic kindreds of the index patient. Fibrinogen is a 340 kDa glycoprotein comprising pairs of three polypeptide chains termed Aα, Bβ, and γ. Fibrinogen has a trinodular structure with a central nodule (E-domain) that contains the N-terminus of each chain and two lateral globular domains (D-domains) that contain the C-terminus of Bβand γ-chains. The E-domain is linked to the two D-domains by a coiled-coil triple helix structure.3,4 The three genes encoding fibrinogen Bβ (FGB), Aα (FGA), and γ (FGG), ordered from centromere to telomere, are clustered in a region of 50 kb on human chromosome 4q28.1,4 Congenital afibrinogenemia is an autosomal recessive bleeding disorder, referring to the total absence of plasma fibrinogen asmeasured by an antigenic assay, and is caused by variations in these genes, and associated with homozygous or compound heterozygous mutations, while hypofibrinogenemia is usually linked with heterozygous mutations.5 Mutations of FGB are less common and of particular interest since the Bβ-chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer.6 The estimated prevalence of congenital afibrinogenemia is 1 in 1,000,000,1 and according to our present knowledge, in Slovakia is 1 in 5,000,000.7 We recently performed genetic analysis of FGA, FGB, and FGG as well as coagulation tests in a patient with congenital afibrinogenemia plus his immediate family (i.e., his parents and two older sisters). The patient with congenital

Activity of coagulation factor XI in patients with spontaneous miscarriage: The presence of risk alleles

Abstract The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients with spontaneous miscarriage versus control group with no history of miscarriage and thrombosis, and then we evaluated the occurrence of risk alleles in the relation to miscarriage. FXI activity was determined using a coagulometer (Sysmex, CA 1500, Japan). Single nucleotide polymorphisms (SNPs) of F11 and CYP4V2 genes were evaluated. We examined 55 patients versus 31 control subjects. We found significantly higher activity of FXI (p = 0.04) in patients versus control subjects. The occurrence of two SNPs (rs2289252 and rs2036914) of the F11 gene and SNP (rs13146272) of CYP4V2 gene was not significantly different between both groups. Increased activity of FXI may be a potential risk factor for miscarriage. High activity of FXI diagnosed in women with history of miscarriage is not probably caused by the presence of studied SNPs.

Endovascular stenting in malignant obstruction of superior vena cava

Highlights • Lymphomas are a common cause of SVCS in young age.• HL may present as SVCS.• Pathological confirmation of diagnosis should be done before initiating therapy while dealing with a case of SVCS.• SVC stenting is effective and has few complications in patients with SVCS.