المؤلفون: Nobuko Nishiura, Yuzuru Kanakura, Kazunobu Kiyomizu, Koichi Kokame, Keigo Akuta, Fumiaki Banno, Hisashi Kato, Yoshiaki Tomiyama, Toshiyuki Miyata, Hirokazu Kashiwagi, Shinji Kunishima

المصدر: Journal of Thrombosis and Haemostasis. 18:497-509

مصطلحات موضوعية: Blood Platelets, medicine.medical_specialty, Integrin, Integrin alpha2, Platelet Glycoprotein GPIIb-IIIa Complex, 030204 cardiovascular system & hematology, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, In vivo, Internal medicine, Gene knockin, medicine, Animals, Humans, Platelet, Thrombopoietin, Mutation, biology, Chemistry, Hematology, Thrombocytopenia, In vitro, Endocrinology, biology.protein, Thrombasthenia

الوصف: Background To date, several mutations that induce constitutive activation of integrin αIIbβ3 have been identified in congenital macrothrombocytopenia. Of these, αIIb(R995W) is the most prevalent mutation observed in Japanese patients with αIIbβ3-related congenital macrothrombocytopenia. Objective and methods The present study aimed to explore the effects of constitutive activation of the αIIb(R995W) mutation on platelet production, morphology, and function. We generated αIIb(R990W) knock-in (KI) mice corresponding to human αIIb(R995W). Results Platelet counts of heterozygous (hetero) and homozygous (homo) KI mice were decreased by ~10% and ~25% relative to those of wild-type (WT) mice, respectively, with increase in platelet size. Decrease in absolute reticulated platelet numbers in steady state, delayed recovery from thrombocytopenia induced by anti-platelet antibody and impaired response to exogenous thrombopoietin administration suggested impaired platelet production in KI mice. WT and KI mice showed no significant differences in the number of megakaryocytes and ploidy of megakaryocytes, whereas proplatelet formation was significantly impaired in homo mice. We observed a slight but significant reduction in platelet lifespan in homo mice. The homo mice showed dramatic reduction in αIIbβ3 expression in platelets, which was accompanied by severe in vivo and in vitro platelet dysfunction. Conclusion The αIIb(R990W) KI mice developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation. In addition, homo KI mice showed marked downregulation in αIIbβ3 expression in platelets with severe impaired platelet function, similar to Glanzmann thrombasthenia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5c1484d22bb6fe424e5ef815af95fbc9Test
https://doi.org/10.1111/jth.14678Test

المؤلفون: Yoshiaki Tomiyama, Hirokazu Kashiwagi, Yuzuru Kanakura, Keigo Akuta, Hisashi Kato, Nobuko Nishiura, Toshiaki Yujiri, Shigenori Honda, Yoichiro Morikawa

المصدر: Journal of Thrombosis and Haemostasis. 17:206-219

مصطلحات موضوعية: medicine.medical_specialty, biology, business.industry, media_common.quotation_subject, Autoantibody, Hematology, 030204 cardiovascular system & hematology, Fibrinogen, Phenotype, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, chemistry, Internal medicine, biology.protein, Medicine, Platelet, Antibody, business, Ristocetin, Internalization, Blood Platelet Disorders, media_common, medicine.drug

الوصف: Essentials Acquired Glanzmann thrombasthenia (aGT) is generally caused by function-blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbβ3 with anti-αIIbβ3 Abs. The anti-αIIbβ3 Abs of the patient did not inhibit platelet function but reduced surface αIIbβ3. Internalization of αIIbβ3 induced by the Abs binding may be responsible for the phenotype. SUMMARY: Background Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function-blocking anti-αIIbβ3 autoantibodies. Aim We characterize an unusual case of aGT caused by marked reduction of surface αIIbβ3 with non-function-blocking anti-αIIbβ3 antibodies (Abs). Methods A 72-year-old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbβ3 expression and genetic analysis were performed. We also analyzed effects of anti-αIIbβ3 Abs of the patient on platelet function and αIIbβ3 expression. Results Surface αIIbβ3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbβ3 to the amount of 40-50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbβ3 expression caused a GT phenotype, and active internalization of αIIbβ3 was suggested. Anti-αIIbβ3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC-1 binding, indicating that the Abs were non-function-blocking. Surface αIIbβ3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbβ3 expression was recovered to 20% of normal with reduction of anti-αIIbβ3 Abs. Conclusion We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbβ3. Internalization induced by anti-αIIbβ3 Abs may be responsible in part for the phenotype.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::67fa4c2548ed35785d56c7bd76f1f0afTest
https://doi.org/10.1111/jth.14323Test

المؤلفون: Yoichiro Morikawa, Hirokazu Kashiwagi, Keigo Akuta, Yuzuru Kanakura, Shigenori Honda, Nobuko Nishiura, Hisashi Kato, Yoshiaki Tomiyama

المصدر: Thrombosis Research. 162:44-52

مصطلحات موضوعية: 0301 basic medicine, MAPK/ERK pathway, Agonist, medicine.medical_specialty, biology, medicine.drug_class, Chemistry, Integrin, Hematology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Thrombin, Endocrinology, Internal medicine, Thrombin receptor, medicine, biology.protein, Platelet, Platelet activation, Receptor, medicine.drug

الوصف: Background Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear. Objectives We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant. To elucidate the role of PAR4 in human platelet activation, we examined if platelet activation induced by PAR4-AP may be associated with PAR4 genotype. Methods Platelets from 202 healthy Japanese volunteers were genetically analyzed and determined the genotype frequency of rs773902. Agonist induced platelet aggregation, integrin αIIbβ3 activation, granule release, Ca2+ mobilization, and activation of ERK and MLC were evaluated. The specificity of effects observed in platelets was confirmed in 293T cells transfected PAR4-Thr120 or Ala120. Results The frequencies of PAR4 variant Thr/Thr120, Ala/Thr120, and Ala/Ala 120 were 5.9, 37.1, and 57.0%, respectively. Platelets with Thr/Thr120 showed significantly higher reactivity in PAR4-AP-induced platelet aggregation, αIIbβ3 activation and granule release compared to platelets with Ala/Ala120. PAR4-AP induced higher Ca2+ mobilization and ERK activation in platelets with Thr/Thr120 than Ala/Ala120. Ca2+ mobilization and ERK activation were also increased in 293T cells transfected with PAR4-Thr120 compared to Ala120. Conclusion Our data suggested that PAR4-AP-induced platelet reactivity between PAR4 rs773902 was associated with altered intensity of Ca2+ mobilization and ERK activation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::17ddb46707c84d03ccedde5930aa747bTest
https://doi.org/10.1016/j.thromres.2017.12.014Test

المؤلفون: Shigenori Honda, Hirokazu Kashiwagi, Yumi Kurokawa, Yozo Nakazawa, Hisashi Kato, Yoshiaki Tomiyama, Daisuke Morita, Fumiaki Banno, Yoichiro Morikawa, Yuzuru Kanakura

المصدر: Blood. 128:2729-2733

مصطلحات موضوعية: 0301 basic medicine, medicine.medical_specialty, Immunology, Integrin, chemistry.chemical_element, 030204 cardiovascular system & hematology, Calcium, Fibrinogen, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Platelet, Hemostatic function, Diacylglycerol kinase, biology, Chemistry, Cell Biology, Hematology, 030104 developmental biology, Endocrinology, Hemostasis, biology.protein, Signal transduction, medicine.drug

الوصف: Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available. Here, we report a 16-year-old girl with CalDAG-GEFI deficiency who has been suffering from severe bleeding tendency. Although talin and kindlin-3 were normally detected, CalDAG-GEFI was undetectable in her platelets by western blotting. Genetic analysis revealed compound heterozygous CalDAG-GEFI mutations, Lys309X and Leu360del, which were responsible for CalDAG-GEFI deficiency. The functional analysis demonstrated impaired αIIbβ3 activation by various agonists except for phorbol myristate acetate, normal calcium mobilization, and impaired Rap1 activation, which were consistent with the phenotype of CalDAG-GEFI-deficient mice. Despite substantial αIIbβ3 activation at high agonist concentrations, she had severe bleeding tendency. Further functional analysis demonstrated markedly delayed αIIbβ3 activation velocity and decreased shear-induced thrombus formation. Contrary to CalDAG-GEFI-deficient mice, which showed integrin-dependent neutrophil functional abnormality, neutrophil β2 integrin activation was not impaired in the patient. Our results demonstrate the critical role of CalDAG-GEFI in rapid αIIbβ3 activation of human platelets.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f92de86d875995876ca254b134eefa4dTest
https://doi.org/10.1182/blood-2016-03-704825Test

المؤلفون: Hideto Nakajima, Tatsuro Ishida, Ryuji Toh, Kazunobu Kiyomizu, Kensuke Kondo, Yasuhiro Irino, Nobuaki Tanaka, Masakazu Shinohara, Junichiro Yamamoto, Yoshiyuki Rikitake, Tomoyuki Yasuda, Takeshige Mori, Tomoko Monguchi, Yoshiaki Tomiyama, Ken-ichi Hirata, Kenta Mori

المصدر: Molecular Nutrition & Food Research. 59:729-740

مصطلحات موضوعية: Male, medicine.medical_specialty, Lipoproteins, Thrombomodulin, Down-Regulation, Inflammation, Biology, Mice, Tissue factor pathway inhibitor, Internal medicine, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Phosphorylation, Endothelial dysfunction, Extracellular Signal-Regulated MAP Kinases, Receptor, Mice, Inbred C3H, Toll-like receptor, JNK Mitogen-Activated Protein Kinases, NF-kappa B, Endothelial Cells, Thrombosis, Trans Fatty Acids, medicine.disease, Toll-Like Receptor 2, Diet, Up-Regulation, Mice, Inbred C57BL, Toll-Like Receptor 4, Disease Models, Animal, Endocrinology, Biochemistry, Cell culture, Endothelium, Vascular, Signal transduction, medicine.symptom, Reactive Oxygen Species, Signal Transduction, Food Science, Biotechnology

الوصف: cope Since excessive intake of trans-fatty acid (TFA) increases the risk of myocardial infarction, we investigated the effects of TFA on thrombus formation using animal and cell culture experiments. Methods and results C57BL/6 mice were fed a diet containing TFA or cis-fatty acid (5% each of total calories) or a chow diet for 4 weeks, and thrombus formation was induced in the carotid artery by He-Ne laser irradiation. The high-TFA diet significantly promoted thrombus formation in the carotid artery compared to the chow or cis-fatty acid diet. TFA activated the inflammatory signaling pathway in cultured endothelial cells and in mice; aortic gene expression levels of antithrombogenic molecules, including thrombomodulin and tissue factor pathway inhibitor, were decreased, and the expression levels of prothrombogenic molecules were increased in TFA-treated mice. TFA markedly upregulated the prothrombogenic molecules and downregulated the antithrombogenic molecules in endothelial cells. In addition, TFA induced phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and nuclear factor-κB. The TFA-activated signal pathways and prothrombogenic phenotypic changes of endothelial cells were inhibited by genetic or pharmacological inactivation of Toll-like receptors 2 and 4. Conclusion TFA aggravates the antithrombogenic phenotypes of vascular endothelial cells via Toll-like receptors and promotes thrombus formation in mice.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::12d8de8d4ea7238258595fad72a17b0bTest
https://doi.org/10.1002/mnfr.201400537Test

المؤلفون: Yoshiaki Tomiyama, Hisashi Kato

المصدر: Autoimmune Thrombocytopenia ISBN: 9789811041419

مصطلحات موضوعية: medicine.medical_specialty, biology, Chemistry, Fibrinogen receptor, medicine.disease, Platelet membrane glycoprotein, Fibrinogen, Endocrinology, Von Willebrand factor, hemic and lymphatic diseases, Internal medicine, medicine, biology.protein, Platelet, GPVI, Hemostatic function, Leukocyte adhesion deficiency, medicine.drug

الوصف: Platelets are small anucleate blood cells that are produced in the bone marrow from the cytoplasm of megakaryocytes. Circulating platelets are essential for primary hemostasis and also involved in pathological thrombosis. For the platelet hemostatic functions, platelet surface membrane glycoproteins are crucial to form platelet-subendothelial matrix and platelet-platelet interactions. At the site of blood vessel injury, platelets are captured by platelet GPIb-IX-V interaction with von Willebrand factor which bound to exposed collagen followed by direct platelet-collagen interaction by GPIa-IIa (integrin α2β1) and GPVI. Platelet fibrinogen receptor GPIIb-IIIa (integrin αIIbβ3) is the most abundant glycoprotein on platelet surface, and its affinity for fibrinogen is tightly regulated by inside-out signaling. The platelet-platelet interaction mediated by activated GPIIb-IIIa is necessary for platelet accumulation on the layer of adhered platelets at the injured vessel. Both quantitative and qualitative abnormalities in these platelet glycoproteins can be a cause of platelet dysfunctions and bleeding disorders. In addition, platelet glycoproteins are also important in the pathogenesis of idiopathic thrombocytopenic purpura (ITP). In the majority of patients with ITP, antiplatelet autoantibodies in plasma are directed against platelet glycoproteins especially GPIIb-IIIa and GPIb-IX-V.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::a9c61fecfd47d74c110792de2988d791Test
https://doi.org/10.1007/978-981-10-4142-6_3Test

المؤلفون: Hisashi Kato, Yoshiaki Tomiyama, Koichi Kokame, Toshiyuki Miyata, Keigo Akuta, Hirokazu Kashiwagi, Yuzuru Kanakura, Nobuko Nishiura

المصدر: Blood. 132:1136-1136

مصطلحات موضوعية: medicine.medical_specialty, Fibrinogen receptor, Chemistry, Glanzmann's thrombasthenia, Platelet disorder, Immunology, Impaired platelet aggregation, Cell Biology, Hematology, medicine.disease, Biochemistry, Platelet Glycoprotein GPIIb-IIIa Complex, P2Y12, Endocrinology, Thrombasthenia, Internal medicine, medicine, Platelet

الوصف: Background and objectives Activation of platelet fibrinogen receptor integrin αIIbβ3 (GPIIb-IIIa) by inside-out signaling is essential for platelet aggregate formation. In αIIbβ3 activation, it has been established that CalDAG-GEFI-induced Rap1 activation is necessary to induce the direct interaction of β3 cytoplasmic tail with talin and kindlin-3. Agonist induced platelet and αIIbβ3 activation are generally assessed using platelet aggregation assay and flow cytometric analysis of monoclonal antibody specific for activated αIIbβ3, PAC-1, binding. However, we found that the results of PAC-1 binding assay were not associated with severity of bleeding symptoms in patient with CalDAG-GEFI (Blood 2016) or ADP receptor P2Y12 (J Thromb Haemost 2005) deficiency. To further determine the role of molecules in inside-out signaling on αIIbβ3 activation and the impact on hemostasis, we studied the αIIbβ3 activation kinetics in patient's platelets deficient for αIIbβ3, P2Y12, CalDAG-GEFI, or kindlin-3 using the αIIbβ3 velocity assay (Exp Hematol 2013). Methods Human platelets were obtained from healthy control subjects and patients with inherited platelet disorders (Glanzmann thrombasthenia, P2Y12 deficiency, CalDAG-GEFI deficiency, and kindlin-3 deficiency). Agonist induced platelet and αIIbβ3 activation were assessed by light transmission aggregometer and PAC-1 binding on flow cytometry. In addition to the conventional PAC-1 binding assay which is simultaneous incubation of stimulated platelets with FITC-PAC-1 for 20 minutes, the time course of αIIbβ3 activation was determined by αIIbβ3 velocity assay. In brief, to measure the activation state of αIIbβ3 at the time of interest (0, 30, 60, 120 and 300 seconds), FITC-labeled PAC-1 was added after the PAR1-AP stimulation. After 30 seconds incubation with FITC-PAC-1, the bound FITC-PAC-1 was immediately assessed by flow cytometry. To determine the thrombus formation under the physiological condition, shear-induced thrombus formation on collagen coated surface was observed. Results In the patient with kindlin-3 deficiency, strongly impaired platelet aggregation and αIIbβ3 activation determined by conventional PAC-1 binding were correlated to the patients severe bleeding problems appeared from early infancy. The αIIbβ3 activation kinetics of kindling-3 deficient platelets showed no PAC-1 binding during 300 seconds after the thrombin receptor agonist PAR1-AP stimulation like platelets of Granzmann thrombasthenia, which suggests the essential role of Kindlin-3 in αIIbβ3 activation. In contrast, in spite of the strongly impaired PAC-1 binding in conventional assay for P2Y12 deficient platelets, the 67 year-old patient showed only minor bleeding symptoms and no transfusion was required during delivery. The αIIbβ3 activation observed in P2Y12 deficiency was transient and the level of initial activation at 30 seconds was the same as healthy control platelets. Under the flow conditions, P2Y12 deficient platelets could form thrombus albeit unstable and fragile. In the 16-yaer-old patient with CalDAG-GEFI deficiency who has been suffering from severe nose bleed and menorrhagia, her platelet aggregation and conventional PAC-1 binding were only modestly affected. The time course of αIIbβ3 activation showed delayed activation. Although αIIbβ3 activation in CalDAG-GEFI deficient platelets reached to similar to that of control at 300 seconds, the initial activation at 30 seconds was significantly decreased to only 19% of control. Her platelets could adhere on collagen under the flow condition. However, almost no aggregate formation was observed which explains her severe bleeding symptoms. Conclusion The analyses of αIIbβ3 activation kinetics in platelets with inherited platelet disorder revealed the importance of immediate and sustained αIIbβ3 activation for hemostasis in physiological conditions. In addition to well established platelet functional assay, the analysis of αIIbβ3 activation kinetics contributes to understand the patient's bleeding symptoms and also clarifies the role of each molecule in inside-out αIIbβ3 activation, CalDAG-GEFI for the immediate activation, P2Y12 for the maintenance of activation, and Kindlin-3 at the last step of αIIbβ3 activation. Disclosures Kanakura: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Tomiyama:Kyowa Hakko Kirin Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sysmex Corporation: Consultancy; Chugai Pharmaceutical Co., Ltd.: Honoraria.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::8d233662ca581edbd046e8679d330967Test
https://doi.org/10.1182/blood-2018-99-112852Test

المؤلفون: Yoshiaki Tomiyama, Yuji Miyajima, Kousaku Matsubara, Junji Suzumiya, Hidehiko Saito, Masafumi Onodera, Makoto Otsu, Shinji Kunishima, Koji Eto, Hirokazu Kashiwagi, Yasushi Takamatsu, Naoya Takayama

المصدر: Blood. 117:5479-5484

مصطلحات موضوعية: Adult, Male, Heterozygote, medicine.medical_specialty, Membrane ruffling, P-selectin, Protein Conformation, DNA Mutational Analysis, Immunology, Integrin alpha2, Mutation, Missense, CHO Cells, Platelet Glycoprotein GPIIb-IIIa Complex, Biology, Transfection, medicine.disease_cause, Biochemistry, Cell Line, Mice, Young Adult, Cricetulus, Cricetinae, Internal medicine, medicine, Animals, Humans, Missense mutation, Platelet, Thrombopoiesis, Platelet activation, Child, Mutation, Integrin beta3, Infant, Fibrinogen binding, Cell Biology, Hematology, Middle Aged, Thrombocytopenia, Recombinant Proteins, Cell biology, Endocrinology, Amino Acid Substitution, Child, Preschool, Female, Mutant Proteins, Megakaryocytes

الوصف: Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. αIIbβ3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of αIIbβ3 in 293T cells was higher for αIIb-W995 than for β3-H723 but was weaker than for β3-N562. FAK was spontaneously phosphorylated in αIIb-W995/β3-transfected 293T cells. These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation. αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective proplatelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a2ef2594e27601b5e66d681d4e409c6eTest
https://doi.org/10.1182/blood-2010-12-323691Test

المؤلفون: Alan T. Nurden, Theodore Kent Gartner, Jianguo Jin, Alexander Georgakis, Yoshiaki Tomiyama, Paquita Nurden, Kamala Bhavaraju, Satya P. Kunapuli

المصدر: Platelets. 21:604-609

مصطلحات موضوعية: medicine.medical_specialty, Aspirin, Prasugrel, biology, Thromboxane, business.industry, Hematology, General Medicine, Pharmacology, Clopidogrel, Endocrinology, P2Y12, Internal medicine, medicine, biology.protein, Platelet, Thromboxane-A synthase, business, Ex vivo, medicine.drug

الوصف: Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of Gi-coupled P2Y12 receptor, respectively. We hypothesized that ADP acting through P2Y12 regulates physiological thromboxane levels. The serum thromboxane levels in mice (n = 3) dosed with clopidogrel and prasugrel were decreased by 83.1 ± 5.3% and 94.26 ± 1.75% respectively compared to untreated mice. Pre-treatment of human blood (n = 3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3 ± 3.2% and 4.9 ± 0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice (n = 4). Whereas serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, those in the P2Y12 null mice were inhibited by 83.15 ± 3.8%. Finally, in a pilot study, serum thromboxane levels ...

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::5c518389d9919ee7a6ac5ffb2a3a23a2Test
https://doi.org/10.3109/09537104.2010.511684Test

المؤلفون: Shosaku Nomura, Yoshiyuki Kurata, Minoru Hasegawa, Masakatsu Nishikawa, Yoshiaki Tomiyama, Kunio Hayashi, Yasuhiro Maeda, Satoshi Higasa, Katsuyasu Saigo, Takayuki Takubo

المصدر: Clinical and Applied Thrombosis/Hemostasis. 16:622-627

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Bone density, medicine.medical_treatment, Osteoporosis, Gastroenterology, Young Adult, Bone Density, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Glucocorticoids, Aged, Retrospective Studies, Bone mineral, Purpura, Thrombocytopenic, Idiopathic, Alendronate, Bone Density Conservation Agents, Diphosphonates, business.industry, Standard treatment, Autoantibody, Hematology, General Medicine, Middle Aged, Bisphosphonate, medicine.disease, Thrombocytopenic purpura, Endocrinology, Quality of Life, Female, business, Glucocorticoid, medicine.drug

الوصف: Immune thrombocytopenic purpura (ITP) is an acquired hemorrhage condition involving accelerated platelet consumption caused by antiplatelet autoantibodies. Although various therapeutic strategies are used to treat patients with ITP, the standard treatment method is steroid therapy. The most important problem with steroid administration may be a prolonged use tendency in many cases, because there are many refractory chronic patients. To elucidate the effects of glucocorticoid on bone mineral density (BMD) in patients with ITP, we retrospectively evaluated the relationship between BMD and the total dose of glucocorticoid or the mean daily dose given. We observed decreased BMD in 66.7% of the patients with ITP to whom glucocorticoid was given, although normal bone BMD was observed in 28.6% of patients with ITP treated without steroids. The mean level of BMD was markedly decreased in steroid-treated patients compared with nonsteroid-treated patients (P < .01). The relationship between BMD and the total dose of glucocorticoid (P = .023) or the mean daily dose revealed a negative correlation (P = .022). Administration of bisphosphonate revealed a significant increase in bone mass in patients at 6 and 12 months after the start of bisphosphonate treatment, despite the aggravation of thrombocytopenia. In conclusion, glucocorticoid-induced osteoporosis was observed in patients with ITP, similar to situation seen in patients with other diseases. Bisphosphonate may be an effective agent for the prevention and treatment of glucocorticoid-induced osteoporosis in patients with ITP scheduled to receive long-term steroid treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::efee30f9d8279ad0f2dcac1be2f2f1e1Test
https://doi.org/10.1177/1076029609350889Test