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Platelet hyperactivation

A Snarska, P Sobiech
The aim of the study was to evaluate the megakaryocyte lineage of bone marrow and coagulation parameters in fallow deer during the last month of pregnancy. The animals were managed in the barn-feeding system. Twenty female fallow deer, aged 2-3 years, divided into 2 groups were used in the study. Group 1 comprised the females in the last month of pregnancy, and the non-pregnant females were used as the control. All the animals were clinically healthy. Coagulation parameters were measured in all the deer: thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and plasma concentrations of fibrinogen, D-dimer, and antithrombin III...
2016: Polish Journal of Veterinary Sciences
Katarina Kapralova, Monika Horvathova, Christian Pecquet, Jana Fialova Kucerova, Dagmar Pospisilova, Emilie Leroy, Barbora Kralova, Jelena D Milosevic Feenstra, Fiorella Schischlik, Robert Kralovics, Stefan N Constantinescu, Vladimir Divoky
The role of somatic JAK2 mutations in clonal myeloproliferative neoplasms (MPNs) is well established. Recently, germ line JAK2 mutations were associated with polyclonal hereditary thrombocytosis and triple-negative MPNs. We studied a patient who inherited 2 heterozygous JAK2 mutations, E846D from the mother and R1063H from the father, and exhibited erythrocytosis and megakaryocytic atypia but normal platelet number. Culture of erythroid progenitors from the patient and his parents revealed hypersensitivity to erythropoietin (EPO)...
September 8, 2016: Blood
Karina Yazdanbakhsh
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder resulting from low platelet counts caused by inadequate production as well as increased destruction by autoimmune mechanisms. As with other autoimmune disorders, chronic ITP is characterized by perturbations of immune homeostasis with hyperactivated effector cells as well as defective regulatory arm of the adaptive immune system, which will be reviewed here. Interestingly, some ITP treatments are associated with restoring the regulatory imbalance, although it remains unclear whether the immune system is redirected to a state of tolerance once treatment is discontinued...
April 2016: Seminars in Hematology
David Pellerin, Artuela Çaku, Mathieu Fradet, Paméla Bouvier, Jean Dubé, François Corbin
AIM: To establish whether platelets from fragile X syndrome (FXS) individuals recapitulate FXS mouse neurons' defects in ERK and Akt pathways, and to evaluate the effect of lovastatin on these pathways. METHODS: ERK and Akt phosphorylation (pERK, pAkt) statuses were assessed with quantitative Western blotting before and after a 12-week lovastatin trial. RESULTS: Levels of pERK and pAkt were increased in FXS platelets, and lovastatin specifically normalized ERK activity...
September 2016: Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals
Chirag Amin, Soheir Adam, Micah J Mooberry, Abdullah Kutlar, Ferdane Kutlar, Denise Esserman, Julia E Brittain, Kenneth I Ataga, Jen-Yea Chang, Alisa S Wolberg, Nigel S Key
Recent epidemiologic data suggest that sickle cell trait (HbAS; AS) is a risk factor for venous thromboembolism. We conducted an exploratory study of healthy subjects with AS under baseline conditions to determine whether a chronic basal hyperactivation of coagulation exists, and if so, what mechanism(s) contribute to this state. Eighteen healthy AS individuals were compared to 22 African-American controls with a normal haemoglobin profile (HbAA; AA) and 17 patients with sickle cell disease (HbSS; SS). Plasma thrombin-antithrombin complexes and D-dimer levels were elevated in AS relative to AA patients (P = 0·0385 and P = 0·017, respectively), and as expected, were much higher in SSversusAA (P < 0·0001 for both)...
November 2015: British Journal of Haematology
Bor Luen Tang
Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells target infected or transformed cells with perforin-containing cytotoxic granules through immune synapses, while platelets secrete several types of granules which contents are essential for thrombosis and hemostasis. Recent work has culminated in the notion that an exocytic SNARE complex, based on a very similar set of components, is primarily responsible for exocytosis of the diverse granules in these different cell types. Granule exocytosis is, in particular, uniquely dependent on the atypical Q-SNARE syntaxin 11, its interacting partners of the Sec/Munc (SM) family, and is regulated by Rab27a...
2015: Molecular Membrane Biology
Samantha F Moore, Christopher M Williams, Edward Brown, Thomas A Blair, Matthew T Harper, Richard J Coward, Alastair W Poole, Ingeborg Hers
AIMS: Patients with conditions that are associated with insulin resistance such as obesity, type 2 diabetes mellitus, and polycystic ovary syndrome have an increased risk of thrombosis and a concurrent hyperactive platelet phenotype. Our aim was to determine whether insulin resistance of megakaryocytes/platelets promotes platelet hyperactivation. METHODS AND RESULTS: We generated a conditional mouse model where the insulin receptor (IR) was specifically knocked out in megakaryocytes/platelets and performed ex vivo platelet activation studies in wild-type (WT) and IR-deficient platelets by measuring aggregation, integrin αIIbβ3 activation, and dense and α-granule secretion...
July 1, 2015: Cardiovascular Research
Peter Kubisz, Lucia Stančiaková, Ján Staško, Peter Galajda, Marián Mokáň
Diabetes mellitus (DM) is an extremely common disorder which carries a risk of vascular impairment. DM type 2 (DM2) can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity. These all are the reasons why DM2 is the most common acquired thrombophilia. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM. As a natural consequence of continuous investigation, many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice...
April 15, 2015: World Journal of Diabetes
Giorgio Bianciardi, Margherita Aglianò, Nila Volpi, Claudia Stefanutti
Familial hypercholesterolemia (FH), a genetic disease, is associated with a severe incidence of athero-thrombotic events, related, also, to platelet hyperreactivity. A plethora of methods have been proposed to identify those activated circulating platelets, none of these has proved really effective. We need efficient methods to identify the circulating platelet status in order to follow the patients after therapeutic procedures. We propose the use of computerized fractal analysis for an objective characterization of the complexity of circulating platelet shapes observed by means of transmission electron microscopy in order to characterize the in vivo hyperactivated platelets of familial hypercholesterolemic patients, distinguishing them from the in vivo resting platelets of healthy individuals...
June 2015: Microscopy Research and Technique
E Véricel, R Colas, C Calzada, Q H Lê, N Feugier, C Cugnet, H Vidal, M Laville, P Moulin, M Lagarde
Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition...
August 2015: Thrombosis and Haemostasis
Clive Bate, Alun Williams
The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage...
2015: Biomolecules
Tatiana E Suslova, Alexei V Sitozhevskii, Oksana N Ogurkova, Elena S Kravchenko, Irina V Kologrivova, Yana Anfinogenova, Rostislav S Karpov
Patients with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) have high risk of microcirculation complications and microangiopathies. An increase in thrombogenic risk is associated with platelet hyperaggregation, hypercoagulation, and hyperfibrinolysis. Factors leading to platelet activation in MetS and T2DM comprise insulin resistance, hyperglycemia, non-enzymatic glycosylation, oxidative stress, and inflammation. This review discusses the role of nitric oxide (NO) in the regulation of platelet adhesion and aggregation processes...
2014: Frontiers in Physiology
Rita C F Duarte, Líllian H Gonçalves, Fernanda M F Campos, Olindo A M Filho, Michelle T Alves, Ana P Fernandes, Karina B G Borges, Luci M S Dusse, Mayara C Faria, Gisele S Gonçalves, Adriana A Bosco, Valéria C Sandrim, Maria G Carvalho
Type 2 diabetes mellitus (DM2) is a metabolic disorder associated with hyperactivation of platelets, increased formation of platelet microparticles (PMPs) and oxidative stress that are related to cardiovascular complications. Acetylsalicylic acid (ASA) is an antiplatelet agent used in the prevention of atherothrombosis. The aim of this study was to evaluate the effect of ASA by means of platelet activation and oxidative profile. We collected blood samples of 81 patients with DM2 before and during ASA treatment...
March 2015: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Dallas S Shi, Matthew C P Smith, Robert A Campbell, Patrick W Zimmerman, Zechariah B Franks, Bjorn F Kraemer, Kellie R Machlus, Jing Ling, Patrick Kamba, Hansjörg Schwertz, Jesse W Rowley, Rodney R Miles, Zhi-Jian Liu, Martha Sola-Visner, Joseph E Italiano, Hilary Christensen, Walter H A Kahr, Dean Y Li, Andrew S Weyrich
The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets...
September 2014: Journal of Clinical Investigation
X Zhang, M A Blaskovich, K D Forinash, S M Sebti
BACKGROUND: The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anticancer agents. METHODS: Co-immunoprecipitation, western blotting, microscopy, DNA binding, invasion, and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin (Wit) inhibits STAT 3/5 tyrosine phosphoryaltion and activation...
August 26, 2014: British Journal of Cancer
Santosh Kumar, Ajit Vikram, Young-Rae Kim, Julia S Jacobs, Kaikobad Irani
BACKGROUND AND HYPOTHESIS: Hypercholesterolemia leads to a prothrombotic phenotype. Platelet hyperactivity associated with hypercholesterolemia has been attributed, in part, to oxidative stress. P66Shc is a well-known determinant of cellular and organismal oxidative stress. However, its role in platelet biology is not known. We hypothesized that p66Shc mediates platelet hyperactivation and hyperaggregation in hypercholesterolemia. METHODS AND RESULTS: P66Shc was expressed in both human and mouse platelets, as determined by qRT-PCR and immunoblotting...
July 11, 2014: Biochemical and Biophysical Research Communications
Shailendra B Patel
PURPOSE OF REVIEW: To provide an update on recent advances made in our mechanistic and pathophysiological understanding of the rare human disease Sitosterolemia, the role of ABCG5/ABCG8 in sterol trafficking and how newer data implicate a more wider role in the body. RECENT FINDINGS: Sitosterolemia is caused by a genetic defect of sterolins (ABCG5/ABCG8) mapped to the STSL locus. Polymorphic variations in STSL have been linked to lipid levels and gallstone disease in whites...
June 2014: Current Opinion in Lipidology
Tanusri Karmakar, Sanjaya K Mallick, Arpita Chakraborty, Animesh Maiti, Subhankar Chowdhury, Maitree Bhattacharyya
Platelet signatures indicating differential dysfunction, hyperactivation, aggregation or adhesion are capable of expressing their characters during the journey of a disease process, and can be utilized as cost effective biomarkers with immense clinical value. Type 2 diabetes mellitus (T2DM) is a major lifestyle disease of contemporary world with progression to diabetes associated cardiovascular diseases (DM-CVD). We identified a few potential biomarkers in platelets of T2DM to analyze the thrombotic risk in diabetes subjects by utilizing flow cytometric quantification with different flurochrome conjugated monoclonal antibodies...
2015: Clinical Hemorheology and Microcirculation
Adriana Fontes Zimmermann, Marcia Margaret Menezes Pizzichini
Systemic Sclerosis (SSc) is an autoimmune disease of multifactorial etiology, triggered by a combination of genetic and environmental factors. Its varied clinical expression results from the complex physiopathogenic interaction of three main elements: proliferative vasculopathy, immune dysregulation and abnormal deposition and remodeling of the extracellular matrix (ECM), of which the characteristic disease fibrosis is the result. Early physiopathogenic events appear to be endothelial injury and imbalance in vascular repair with the activation of endothelial cells, the immune system and platelets, with the release of multiple mediators such as TH2 proinflammatory cytokines and growth factors, triggering a sequence of simultaneous or cascading events that involve several intracellular signaling pathways...
November 2013: Revista Brasileira de Reumatologia
Wai Ho Tang, Jeremiah Stitham, Yu Jin, Renjing Liu, Seung Hee Lee, Jing Du, Gourg Atteya, Scott Gleim, Geralyn Spollett, Kathleen Martin, John Hwa
BACKGROUND: Platelet abnormalities are well-recognized complications of diabetes mellitus. Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in diabetes mellitus. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in platelets in diabetes mellitus is unknown. METHODS AND RESULTS: Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase activation and subsequent reactive oxygen species production lead to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage, and rupture by sequestration of the antiapoptotic protein Bcl-xL...
April 15, 2014: Circulation
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