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Reduced inhibition by abciximab in platelets with the PI^A2 polymorphism

AMERICAN HEART JOURNAL 2002年第1期143卷 76-82页

作者： Wheeler, GL Braden, GA Bray, PF Marciniak, SJ Mascelli, MA Sane, DC Wake Forest Univ Sch Med Sect Cardiol Winston Salem NC 27157 USA Baylor Coll Med Thrombosis Res Sect Houston TX USA Centocor Inc Dept Clin Pharmacol Malvern PA USA

Background The Pl(A2) polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. Methods Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 pl(A1)/(A1) and 21 pl(Al)/(A2) patients undergoing percutaneous coronary interventions. The affinity of abciximab for the pl(A1) and Pl(A2) receptors was determined with use of transfected cells. Results Compared with pl(A1)/(A1) homozygotes, pl(A1/A2) platelets were less completely inhibited after abciximab bolus (P =.002) and at 24 hours (P =.02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that plAl/A2 platelets were less completely inhibited after abciximab bolus (P =.05). The radiometric abciximab binding assay demonstrated that the pl(A1/A2) platelets had fewer baseline fibrinogen receptors than did the pl(A1/A1) platelets (P = .04) and more free fibrinogen receptors at 2.4 hours (P = .008). Cells transfected to express homozygous pl(A1) or pl(A2) demonstrated a nonsignificant trend (P = .12) for reduced abciximab affinity for pl(A2). Conclusions pl(A1/A2) platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of pl(A2)-positive platelets may contribute to a less favorable outcome in these patients.

关键词：抗体单克隆/代谢抗体单克隆/治疗应用抗原人血小板/遗传学抗原人血小板/代谢血小板/药物作用血小板/代谢 CHO细胞仓鼠亚科免疫球蛋白Fab片段/代谢免疫球蛋白Fab片段/治疗应用血小板糖蛋白GPⅡb-Ⅲa复合物/拮抗剂和抑制剂血小板糖蛋白GPⅡb-Ⅲa复合物/遗传学多态现象遗传转染成年人老年人老年人 80以上动物女(雌)性人类男(雄)性中年人

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Effects of a novel non-carboxylic thromboxane A₂ receptor antagonist (BM-531) derived from torasemide on platelet function

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PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS 2000年第5期62卷 311-317页

作者： Dogné, JM de Leval, X Neven, P Rolin, S Wauters, J David, JL Delarge, J Masereel, B Univ Liege Dept Med Chem B-4000 Liege Belgium Univ Namur Dept Pharm B-5000 Namur Belgium Univ Namur Dept Mol & Struct Chem B-5000 Namur Belgium Univ Hosp Dept Thrombosis & Hemostasis B-4000 Liege Belgium

In this study we examined the thromboxane A(2) (TXA(2)) receptor antagonist property of BM-531 (N-tert-butyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonl]urea), a torasemide derivative, on platelet function. The drug affinity for human washed platelet TXA(2) receptors labelled with [H-3]SQ-29,548 has been determined (IC50: 0.0078 mu M) and demonstrated to be higher than sulotroban (IC50: 0.93 mu M) and SQ-29,548 (IC50: 0.021 mu M). The antiaggregatory potency has been confirmed since we demonstrated that BM-531 prevented platelet aggregation in human citrated platelet-rich plasma induced by arachidonic acid (600 mu M) (ED100: 0.125 mu M), U-46619, a stable TXA(2) agonist (1 mu M) (ED50: 0.482 mu M) and collagen (1 mu g ml(-1)) (% of inhibition: 42.9% at 10 mu M) and inhibited the second wave of ADP (2 mu M). Moreover, when BM-531 was incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100(R)) was significantly prolonged. These results suggest that BM-531 can be regarded as a novel non-carboxylic TXA(2) antagonist with a powerful antiplatelet potency. (C) 2000 Harcourt Publishers Ltd.

关键词：腺苷二磷酸/药理学结合竞争性血小板/代谢剂量效应关系药物脂肪酸类不饱和止血/药物作用肼类/代谢半数抑制浓度分子结构血小板聚集/药物作用血小板聚集抑制剂/药理学受体血栓烷/拮抗剂和抑制剂磺胺类/化学磺胺类/代谢磺胺类/药理学磺酰脲化合物/药理学时间因素人类

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The effect of storage on the expression of platelet membrane phosphatidylserine and the subsequent impact on the coagulant function of stored platelets

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TRANSFUSION 2000年第10期40卷 1257-1263页

作者： Shapira, S Friedman, Z Shapiro, H Presseizen, K Radnay, J Ellis, MH Meir Hosp Blood Bank Dept Med B IL-44281 Kefar Sava Israel Meir Hosp Hematol Lab IL-44281 Kefar Sava Israel Meir Hosp Dept Geriatr IL-44281 Kefar Sava Israel Meir Hosp Div Transfus Med IL-44281 Kefar Sava Israel Tel Aviv Univ Sackler Sch Med IL-69978 Tel Aviv Israel Bar Ilan Univ Fac Life Sci Ramat Gan Israel

BACKGROUND: Platelet concentrates (PCs) derived from whole blood and stored under standard blood bank conditions undergo changes that are referred to as the platelet storage lesion. This study assesses the effect of PC preparation and storage on the distribution of phosphatidylserine (PS) in the platelet membrane and the effect that this distribution may have on the thrombogenic potential of stored PCs. STUDY DESIGN AND METHODS: Fresh platelets and PCs donated by healthy donors were obtained. PCs derived from platelet-rich plasma were studied on Day 1, Day 3, and Day 6 of storage under blood bank conditions. RESULTS: Platelet aggregation after exposure to the platelet agonists ADP and epinephrine singly declined progressively, but, when ADP and epinephrine in combination and collagen and thrombin in combination were used as agonists, the decline in platelet aggregation was less marked. PS expression as measured by Annexin V binding (mean and SD) was 2.02 +/- 0.93 percent in fresh platelet samples and increased to 5.39 +/- 4.2 percent on Day 1, 22.1 +/- 7.1 percent on Day 3, and 39.5 +/- 12.1 percent on Day 6. Platelet prothrombinase activity (mean +/- SD) as measured by thrombin generation increased from 1.49 +/- 0.7 mu per mL in fresh platelet samples to 3.68 +/- 1.1 mu per mL in Day 1 platelets (p<0.001), 5.15 +/- 2.5 mu per mL in Day 3 platelets (p<0.001), and 4.65 +/- 2.48 mu per mL in Day 6 platelets (p<0.001). CONCLUSION: These results show that PS expression increases after preparation of PCs from platelet-rich plasma and rises progressively during platelet storage under blood bank conditions. Furthermore, the greater PS expression is associated with increased platelet-dependent thrombin-generating capacity.

关键词：血液凝固/药物作用血液凝固/生理学血小板/药物作用血小板/酶学血小板/代谢血液保存磷脂酰丝氨酸类/生物合成血小板活化/药物作用血小板聚集/药物作用凝血酶/生物合成凝血致活酶/代谢人类

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Synthesis of 19-[(2-azido-5-iodo)-benzoyloxy]-LTA₄ and enzymatic conversion to the LTC₄ analogue

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第7期10卷 665-668页

作者： Vidal, A Durand, T Vidal, JP Rossi, JC Ravasi, S Zarini, S Sala, A Univ Montpellier 1 CNRS Lab Chim Biomol & Interact Biol Associe Fac Pharm F-34060 Montpellier France Univ Milan Inst Pharmacol Sci I-20133 Milan Italy

New photoaffinity probes based on C-19 position of leukotriene A(4) has been synthesized from 19-hydroxy-LTA(4) methyl ester. Enzymatic conversion into the LTC4 analogue yielded a potential tool for the study of cys-L... 详细信息

关键词：血小板/酶学血小板/代谢谷胱甘肽转移酶/代谢白三烯A4/类似物和衍生物白三烯A4/化学合成白三烯A4/代谢白三烯C4/类似物和衍生物白三烯C4/化学合成白三烯C4/化学有机锡化合物/化学合成有机锡化合物/代谢人类

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EFFECT OF ARACHIDONIC-ACID ON SOME INHIBITORS OF HUMAN PLATELET-RELEASE REACTION

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BIOCHEMICAL PHARMACOLOGY 1978年第17期27卷 2131-2138页

作者： LEONARDI, RG ALEXANDER, B WHITE, F PARTS, A NEW YORK BLOOD CTR LINDSLEY F KIMBALL RES INST COAGULAT LAB NEW YORK NY 10021 USA

The inhibitory action of many agents on platelet aggregation and 5-hydroxy-tryptamine [5 HT] release inducible by epinephrine, comprising several non-steroidal anti-inflammatory drugs (NSAA), indomethacin, acetylsalicylic acid, sodium salicylate, phenylbutazone and sulfinpyrazone, and other non-anti-inflammatory agents (NAA), prostaglandin E1, adenosine, dipyridamole, methysergide and cyproheptadine could be prevented, and under special circumstances reversed, by the prior addition to human platelet rich plasma of the essential fatty acid, 5,8,11,14 eicosatetraenoic (arachidonic) acid. Although this agent, and only its all cis stereosiomeric form, could induce aggregation and release, its protective action against the platelet-toxic drugs was attributed to its role as the key substance essential for prostaglandin enzymatic biosynthesis. The mechanism of NSAA action was evidently different from that of the non-anti-inflammatory agents.

关键词：腺苷二磷酸/药理学花生四烯酸类/药理学阿司匹林/药理学血小板/药物作用血小板/代谢依地酸/药理学肾上腺素/药理学血清素/代谢人类

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Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

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NATURE GENETICS 1999年第2期23卷 166-175页

作者： Song, WJ Sullivan, MG Legare, RD Hutchings, S Tan, XL Kufrin, D Ratajczak, J Resende, IC Haworth, C Hock, R Loh, M Felix, C Roy, DC Busque, L Kurnit, D Willman, C Gewirtz, AM Speck, NA Bushweller, JH Li, FP Gardiner, K Poncz, M Maris, JM Gilliland, DG Brigham & Womens Hosp Dept Med Boston MA 02115 USA Harvard Univ Sch Med Dana Farber Canc Inst Boston MA 02115 USA Brown Univ Women & Infants Hosp Program Womens Oncol Providence RI USA Univ Penn Sch Med Dept Pediat Philadelphia PA 19104 USA Univ Penn Sch Med Dept Med Philadelphia PA 19104 USA Leicester Royal Infirm Leicester Leics England St Vincent Hosp Childrens Ctr Canc & Blood Dis Indianapolis IN USA Univ Montreal Maisonneuve Rosemont Hosp Dept Hematol Montreal PQ H3C 3J7 Canada Univ Montreal Maisonneuve Rosemont Hosp Res Ctr Montreal PQ H3C 3J7 Canada Univ Michigan Med Ctr Dept Pediat Ann Arbor MI 48109 USA Univ Michigan Med Ctr Dept Human Genet Ann Arbor MI 48109 USA Univ New Mexico Sch Med Dept Pathol Albuquerque NM 87131 USA Univ New Mexico Sch Med Ctr Canc Albuquerque NM 87131 USA Dartmouth Coll Hitchcock Med Ctr Dartmouth Med Sch Dept Biochem Hanover NH 03756 USA Univ Virginia Dept Mol Physiol & Biol Phys Charlottesville VA USA Eleanor Roosevelt Inst Denver CO USA Harvard Univ Sch Med Howard Hughes Med Inst Boston MA 02115 USA

Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

关键词：氨基酸序列碱基序列血小板/代谢染色体图集落形成单位测定核心结合因子α2亚基 DNA突变分析 DNA结合蛋白质类家庭卫生疾病遗传易感性基因型血细胞生成/遗传学杂合子原位杂交荧光巨核细胞/细胞学巨核细胞/代谢微卫星重复分子序列数据突变系谱原癌基因蛋白质类 RNA/遗传学 RNA/代谢逆转录聚合酶链反应序列缺失序列同源性氨基酸序列同源性核酸血小板减少/遗传学转录因子/遗传学女(雌)性人类男(雄)性

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Generation and rescue of a murine model of platelet dysfunction: The Bernard-Soulier syndrome

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第6期97卷 2803-2808页

作者： Ware, J Russell, S Ruggeri, ZM Scripps Res Inst Dept Mol & Expt Med Roon Res Ctr Arteriosclerosis & Thrombosis Div Expt Hemostasis & Thrombosis La Jolla CA 92037 USA Scripps Res Inst Dept Vasc Biol Roon Res Ctr Arteriosclerosis & Thrombosis Div Expt Hemostasis & Thrombosis La Jolla CA 92037 USA

The human Bernard-Soulier syndrome is an autosomal recessive disorder of platelet dysfunction presenting with mild thrombocytopenia, circulating "giant" platelets and a bleeding phenotype, The bleeding in patients with the Bernard-Soulier syndrome is disproportionately more severe than suggested by the reduced platelet count and is explained by a defect in primary hemostasis owing to the absence of the platelet glycoprotein (GP) Ib-IX-V membrane receptor. However, the molecular basis for the giant platelet phenotype and thrombocytopenia have remained unresolved but assumed to be linked to an absent receptor complex. We have disrupted the gene encoding the a-subunit of mouse CP Ib-IX-V (GP Ib alpha) and describe a murine model recapitulating the hallmark characteristics of the human Bernard-Soulier syndrome. The results demonstrate a direct link between expression of a CP Ib-IX-V complex and normal megakaryocytopoiesis and platelet morphogenesis, Moreover, using transgenic technology the murine Bernard-Soulier phenotype was rescued by expression of a human CP Ib alpha subunit on the surface of circulating mouse platelets. Thus, an in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets.

关键词： Bernard-Soulier综合征/遗传学 Bernard-Soulier综合征/病理学血小板/代谢血小板/病理学印迹法 RNA 印迹法 DNA 疾病模型动物流式细胞术基因缺失基因型巨核细胞/代谢小鼠转基因显微镜检查电子诱变定点表型血小板糖蛋白GPⅠb-Ⅸ复合物/遗传学血小板糖蛋白GPⅠb-Ⅸ复合物/代谢血小板糖蛋白GPⅠb-Ⅸ复合物/生理学动物人类小鼠

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A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic

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THROMBOSIS AND HAEMOSTASIS 1999年第2期81卷 306-311页

作者： Kawasaki, T Kaida, T Arnout, J Vermylen, J Hoylaerts, MF Katholieke Univ Leuven Ctr Mol & Vasc Biol B-3000 Louvain Belgium

The thrombotic risk associated with elevated plasma levels of clotting factor VIII (FVIII) was investigated in a mouse model of thrombophilia. After the intravenous injection of recombinant human FVIII and/or of purified FVIII-free human von Willebrand factor (VWF), a controlled mild injury was inflicted on the carotid artery of FVB mice by irradiation with filtered green light in combination with intravenous injection of the dye rose bengal. Formation of a platelet-rich thrombus was continuously monitored for 40 min via transillumination and the thrombus size was measured via image analysis. Administration of recombinant human FVIII at 40 mu g/kg led to initial FVIII plasma activities equivalent to 250% of normal human plasma FVIII activity and significantly enhanced thrombus size. Immunohistochemical staining illustrated the accumulation of FVIII within the thrombi. Human vWF, even at 10 mg/kg, had no effect on thrombus formation. The thrombotic tendency induced by FVIII was significantly inhibited by the administration of human VWF in a dose-dependent manner. Separate plasma measurements revealed that human FVIII has comparable affinities for human and murine vWF but that human vWF does not effectively bind murine platelets. The inhibition by human vWF of the thrombotic tendency induced by human FVIII could therefore be explained by a lack of accumulation of FVIII within the developing thrombus because of the reduced affinity of human vWF for murine platelets and the reduced occupancy of murine von Willebrand factor by human FVIII after injection of human vWF. These results show that vWF actively participates in FVIII accumulation in the arterial thrombus and provide experimental evidence for epidemiological findings that elevated plasma FVIII levels are associated with an increased thrombotic risk, also in arteries.

关键词：血小板/代谢颈动脉血栓形成/化学诱导颈动脉血栓形成/病因学疾病模型动物因子Ⅷ/分析因子Ⅷ/代谢因子Ⅷ/毒性光光化学蛋白质结合重组融合蛋白质类/治疗应用重组融合蛋白质类/毒性危险因素玫瑰红/毒性种特异性血栓形成倾向/血液血栓形成倾向/流行病学 vonWillebrand因子/代谢 vonWillebrand因子/治疗应用动物女(雌)性人类男(雄)性小鼠

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EFFECT OF VITAMIN-B6 ON LEUCINE-INDUCED CHANGES IN HUMAN SUBJECTS

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AMERICAN JOURNAL OF CLINICAL NUTRITION 1976年第2期29卷 177-181页

作者： KRISHNASWAMY, K RAO, SB RAGHURAM, TC SRIKANTIA, SG INDIAN COUNCIL MED RES NATL INST NUTR HYDERABAD 500007 INDIA

Disturbances in the tryptophan-niacin pathway seen in endemic pellagra among sorghum eaters have been ascribed to high dietary intake of leucine. Vitamin B6 plays an important role in several steps of this pathway. Studies on possible metabolic interrelations between excess dietary leucine and vitamin B6 were undertaken in normal healthy subjects. Vitamin B6 could successfully counteract the effects of leucine on quinolinic acid excretion in urine and on in vitro nicotinamide nucleotide synthesis by erythrocytes. Vitamin B6 also could correct the abnormalities of 5-hydroxytryptamine metabolism induced by excess leucine. Vitamin B6 nutritional status may have a contributory role in the pathogenesis of endemic pallagra.

关键词：血小板/代谢药物协同作用红细胞/代谢摄食行为羟基吲哚乙酸/尿印度亮氨酸/药理学烟酸类/代谢糙皮病/病因学吡多辛/药理学喹啉酸类/尿核糖核苷酸类/血液血清素/血液色氨酸/代谢成年人人类男(雄)性

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von Willebrand factor conformation and adhesive function is modulated by an internalized water molecule

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NATURE STRUCTURAL BIOLOGY 2000年第10期7卷 881-884页

作者： Celikel, R Ruggeri, ZM Varughese, KI Scripps Res Inst Dept Mol & Expt Med Div Expt Hemostasis & Thrombosis Roon Res Ctr Arteriosclerosis & Thrombosis La Jolla CA 92037 USA Scripps Res Inst Dept Vasc Biol La Jolla CA 92037 USA

Platelet participation in hemostasis and arterial thrombosis requires the binding of glycoprotein (GP) Ib alpha to von Willebrand factor (vWF). Hemodynamic forces enhance this interaction, an effect mimicked by the substitution 1546V in the VWF A1 domain. A water molecule becomes internalized near the deleted lie methyl group. The change in hydrophobicity of the local environment causes positional changes propagated over a distance of 27 Angstrom. As a consequence, a major reorientation of a peptide plane occurs in a surface loop involved in GP Ib alpha binding. This distinct vWF conformation shows increased platelet adhesion and provides a structural model for the initial regulation of thrombus formation.

关键词：血小板/细胞学血小板/代谢细胞黏附/生理学模型分子蛋白质结合蛋白质构象水/化学 vonWillebrand因子/化学 vonWillebrand因子/代谢 vonWillebrand因子/生理学

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