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Elevated plasma fibrinogen and increased fibrin turnover among healthy women who both smoke and use low-dose oral contraceptives - A preliminary report

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1112-1116页

作者： Scarabin, PY Vissac, AM Kirzin, JM Bourgeat, P Amiral, J Agher, R Guize, L Hop Paul Brousse Cardiovasc Epidemiol Unit U2258 INSERM F-94807 Villejuif France Lab Serblo Gennevilliers France Ctr Invest Prevent & Clin IPC Paris France

Among users of low-dose oral contraceptives (OC), cardiovascular diseases occur mainly in smokers. The mechanisms by which OC and smoking increase the risk for arterial thrombotic risk have not been adequately explained. Epidemiological evidence suggests that changes in blood coagulation and fibrinolysis may play an important role as determinants of thrombotic events. Therefore, we have investigated the associations of OC and smoking with haemostatic variables among 194 premenopausal healthy women. Fourty women were current users of low-dose OC and 62 women were smokers. After adjustment for age and body mass index, mean values of factor XIIa, factor VII activity and antigen. fibrinogen, D-dimer, global fibrinolytic capacity were significantly higher in OC users than in non-users, Mean levels of PAI activity and t-PA antigen were significantly lower in OC users than in non-users. Smokers had significantly higher mean values of fibrinogen than non-smokers. Two-way analysis of variance showed that the differences in mean levels of fibrinogen and D-dimer between OC users and non users were restricted to smokers. The positive and significant interactions between OC use and smoking in their effects on haemostatic variables were consistent with respect to age and type Of OC. These preliminary data suggest that elevated plasma levels of fibrinogen and intravascular fibrin deposition may play a role in the pathogenesis of arterial thrombotic disease among women who are both low-dose OC users and smokers.

关键词：心血管疾病/血液心血管疾病/病因学避孕药口服/投药和剂量纤维蛋白/代谢纤维蛋白原/代谢纤维蛋白溶解/药物作用纤维蛋白溶解/生理学止血/药物作用止血/生理学危险因素吸烟/血液成年人女(雌)性人类中年人

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Pravastatin therapy in hyperlipidemia: Effects on thrombus formation and the systemic hemostatic profile

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第5期33卷 1294-1304页

作者： Dangas, G Badimon, JJ Smith, DA Unger, AH Levine, D Shao, JH Meraj, P Fier, C Fallon, JT Ambrose, JA Mt Sinai Sch Med Dept Med New York NY 10029 USA Mt Sinai Sch Med Dept Pathol New York NY 10029 USA Cornell Univ Coll Med Rogosin Inst New York NY USA

OBJECTIVES The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. BACKGROUND Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. METHODS We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. RESULTS Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F-1.2, factor Wa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed

关键词：阿司匹林/治疗应用血液凝固因子/代谢胆固醇 LDL/血液冠状动脉血栓形成/血液冠状动脉血栓形成/药物疗法冠状动脉血栓形成/病因学双盲法纤维蛋白溶解药/治疗应用随访研究止血/药物作用羟甲基戊二酰基CoA还原酶抑制剂/治疗应用高脂血症/血液高脂血症/并发症高脂血症/药物疗法脂蛋白(A)/血液普伐他丁/治疗应用前瞻性研究治疗结果老年人女(雌)性人类男(雄)性中年人

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o-raffinose cross-linked hemoglobin improves the hemostatic defect associated with anemia and thrombocytopenia in rabbits

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BLOOD 2000年第10期96卷 3630-3636页

作者： Lee, DH Bardossy, L Peterson, N Blajchman, MA Queens Univ Div Hematol Dept Med Kingston ON K7L 3N6 Canada Queens Univ Dept Pathol Kingston ON K7L 3N6 Canada McMaster Univ Dept Pathol & Mol Med Hamilton ON L8S 4L8 Canada

Several different preparations of crosslinked hemoglobin (CLHb) are being evaluated for their efficacy and safety as red cell substitutes in a variety of preclinical and clinical settings. Because CLHb is known to sequester nitric oxide (NO) and inhibit NO-mediated processes, we hypothesized that CLHb would have a hemostatic effect by enhancing platelet reactivity, inducing vasoconstriction, or both. Infusion of o-raffinose CLHb shortened the prolonged microvascular bleeding time and decreased blood loss from ear incisions in rabbits rendered anemic and thrombocytopenic, Moreover, this hemostatic effect persisted for at least 24 hours after infusion. Phenylephrine induced a degree of vasoconstriction similar to that induced by CLHb but did not shorten the bleeding time or decrease blood loss, suggesting that vasoconstriction alone cannot account for the hemostatic effect of CLHb, There was no evidence of CLHb-induced activation of coagulation in vivo, since infusion of CLHb did not increase circulating levels of thrombin-antithrombin complex. In vitro, CLHb abolished the inhibitory effect of the NO donor 3-morpholinosydnonimine on platelet aggregation and enhanced the aggregation of stimulated but not resting platelets, This potentiating effect was not attenuated by the addition of superoxide dismutase or catalase. To evaluate the potential arterial thrombogenicity of CLHb, a model of carotid artery thrombosis was developed in rabbits without thrombocytopenia or anemia. Compared with albumin infusion, CLHb infusion shortened the time to complete carotid occlusion, These data suggest that CLHb may shift the thromboregulatory balance toward clot formation, resulting in decreased bleeding in anemic and thrombocytopenic rabbits and possibly increasing arterial thrombogenicity in normal rabbits. (C) 2000 by The American Society of Hematology.

关键词：肾上腺素能α激动剂/药理学贫血/血液抗凝血酶Ⅲ/药物作用出血时间颈动脉血栓形成/血液颈动脉血栓形成/化学诱导颈动脉血栓形成/药物疗法交联试剂/代谢交联试剂/药理学疾病模型动物剂量效应关系药物血红蛋白类/代谢血红蛋白类/药理学出血止血/药物作用动力学微循环/药物作用肽水解酶类/药物作用苯福林/药理学血小板聚集/药物作用棉子糖/代谢棉子糖/药理学大鼠 Sprague-Dawley 血清白蛋白/药理学血小板减少/血液血管收缩/药物作用动物男(雄)性兔大鼠

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Fibrin specificity and procoagulant effect related to the kallikrein-contact phase system and to plasmin generation with double-bolus reteplase and front-loaded alteplase thrombolysis in acute myocardial infarction

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AMERICAN JOURNAL OF CARDIOLOGY 2000年第3期86卷 263-268页

作者： Hoffmeister, HM Kastner, C Szabo, S Beyer, ME Helber, U Kazmaier, S Baumbach, A Wendel, HP Heller, W Univ Tubingen Med Klin Abt Innere Med 3 D-72076 Tubingen Germany

This study was undertaken to compare the effects of reteplase and alteplase regimens on hemostasis and fibrinolysis in acute myocardial infarction (AMI). Thrombolytic treatment in patients with AMI is hampered by paradoxical procoagulant effects that favor early reocclusion. In vivo data comparing this effect and the fibrin specificity of double-bolus reteplase and front-loaded alteplase regimens are not available. In a prospective, randomized study, 50 patients with AMI were either treated with double bolus (10 + 10 U) reteplase or with front-loaded alteplase (up to 100 mg) within 6 hours of symptom onset. Thirty apparently healthy persons served as controls. Molecular markers of coagulation and fibrinolysis were serially examined for up to 5 days. Paradoxical thrombin activation at 3 hours after initiation of therapy was comparable between reteplase and alteplase. Reteplase (65 +/- 5 U/L) and alteplase (72 +/- 8 U/L) caused significantly elevated kallikrein activity at 3 hours after adminstration (p <0.01 vs controls 30 +/- 1 U/L). Fibrin specificity was less for reteplase (p <0.05) with a decrease in fibrinogen at 3 hours to 122 +/- 27 mg/dl versus 224 +/- 28 mg/dl for alteplase (p <0.01 and p <0.05 vs controls). D-Dimer levels at 3 hours were higher (p <0.05) after reteplase (5,459 +/- 611 ng/ml) versus alteplase (3,445 +/- 679 ng/ml) (both p <0.01 vs controls 243 +/- 17 ng/ml). Plasmin generation (plasmin-antiplasmin complexes) was significantly (p <0.01) increased at 3 hours with both regimens to 27,079 +/- 3,964 mu g/L (reteplase) and 19,522 +/- 2,381 mu g/L (alteplase). The data from 3 hours after start of thrombolytic therapy proved less marked fibrin specificity of the reteplase regimen (in vivo) compared with front-loaded alteplase. Both regimens have a moderate procoagulant effect without differences in activation of the kallikrein system.

关键词：抗凝血酶Ⅲ/药物作用抗凝血酶Ⅲ/代谢剂量效应关系药物用药计划表药物疗法联合纤维蛋白/药物作用纤维蛋白/代谢纤维蛋白溶解/药物作用纤维蛋白溶解药/投药和剂量止血/药物作用激肽释放酶类/药物作用激肽释放酶类/代谢心肌梗死/血液心肌梗死/药物疗法肽水解酶类/药物作用肽水解酶类/代谢纤溶酶/代谢前瞻性研究重组蛋白质类/投药和剂量复发凝血酶/代谢血栓溶解疗法组织型纤溶酶原激活物/投药和剂量成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Haemostatic effects of low osmolar non-ionic and ionic contrast media: a double-blind comparative study

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BRITISH JOURNAL OF RADIOLOGY 2000年第867期73卷 248-255页

作者： Hoffmann, JJML Tielbeek, AV Krause, W Catharina Hosp Dept Clin Labs NL-5602 ZA Eindhoven Netherlands Catharina Hosp Dept Radiol NL-5602 ZA Eindhoven Netherlands Schering AG Dept Contrast Media Res D-1000 Berlin Germany

In this prospective, double-blind, randomized study the effects of a non-ionic contrast medium (Iopromide) on the haemostatic system were compared with those of a low osmolar ionic medium (Ioxaglate). The aim was to investigate in vivo whether a non-ionic contrast agent is less anticoagulant or more pro-thrombotic than an ionic medium. A large number of haemostatic parameters, including activation markers, were measured. Either Iopromide (n=16;median volume 102 ml, 95% confidence interval 90-108 ml) or Ioxaglate (n=15;median 105 ml;95% confidence interval 95-114 ml) was given to 31 patients scheduled for abdominal and femoral arteriography. Blood for laboratory investigations was collected before, and 5 and 30 min after, administering the contrast medium. Indications for activation of coagulation and platelets were already found in nearly 50% of the patients before any contrast medium was given. Both Iopromide and Ioxaglate caused further increases in thrombin-antithrombin complex, prothrombin fragments 1+2 and beta-thromboglobulin. The degree of activation was similar for both agents. Anticoagulant effects were not observed. The haemorheological effects were compatible with haemodilution by 5-8%, again without differences between the contrast agents. Contrary to the findings from in vitro studies, we found no significant differences between the effects of the non-ionic Iopromide and the ionic Ioxaglate on coagulation and platelets. Both agents activated these systems to a limited, but identical, degree. Our results support the notion that the catheterization procedure pet sc may represent a source of haemostatic activation and that the ionic contrast agent studied has insufficient anticoagulant effect to prevent clotting activation being induced by the contrast medium.

关键词：血液凝固/药物作用血小板/药物作用造影剂/药理学双盲法止血/药物作用碘海醇/类似物和衍生物碘海醇/药理学碘克沙酸/药理学成年人老年人女(雌)性人类男(雄)性中年人

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A human antibody that binds to the γ-carboxyglutamic acid domain of factor IX is a potent antithrombotic in vivo

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1188-1195页

作者： Refino, CJ Himber, J Burcklen, L Moran, P Peek, M Suggett, S Devaux, B Kirchhofer, D Genentech Inc Dept Cardiovasc Res San Francisco CA 94080 USA Genentech Inc Antibody Technol Dept San Francisco CA 94080 USA F Hoffmann La Roche & Co Ltd Preclin Res CH-4002 Basel Switzerland

10C12, a human antibody F(ab')(2), which specifically binds to the Gla domain of factor IX, interfered with all known coagulation processes that involve factor IX/IXa. These include the function of the intrinsic Xase complex and the activation of zymogen factor IM by factor XIa and by the tissue factor:factor VIIa complex, Furthermore, 10C12 potently inhibited activated partial thromboplastin clotting times (APTT) in plasma of guinea pig and rat, thus enabling in-vivo evaluation. In guinea pigs, a bolus administration of 10C12 (10 mu g/kg) prevented cyclic flow variations in damaged carotid arteries without affecting coagulation or bleeding parameters. At a 100-fold higher dose, 10C12 had no effect on normal hemostasis as assessed by the cuticle bleeding time. At this dose, 10C12 was also efficacious in a rat arterial thrombosis model, substantially reducing clot weight and duration of vessel occlusion while prolonging ex-vivo APTT only 1.2-fold. The dose of heparin required to produce comparable antithrombotic effects prolonged the APTT by 12-fold and increased the tail bleeding time (TBT) by 8-fold. In contrast, 10C12 had no effect on TBT. However, rat tails showed a tendency for rebleeding which 10C12 exacerbated. In conclusion, the antithrombotic potency of the 10C12 antibody in two species provides evidence for an important role of ***, and its Gla domain in particular, during thrombogenesis under arterial flow conditions. The relative safety at effective doses of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.

关键词： 1-羧基谷氨酸/免疫学结合部位血液凝固/药物作用疾病模型动物因子Ⅸ/拮抗剂和抑制剂因子Ⅸ/免疫学因子Ⅸ/代谢纤维蛋白溶解药/代谢纤维蛋白溶解药/药理学止血/药物作用肝素/药理学免疫球蛋白Fab片段/代谢免疫球蛋白Fab片段/药理学大鼠 Sprague-Dawley 血栓形成/血液血栓形成/治疗动物豚鼠人类男(雄)性大鼠

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The structure of leech anti-platelet protein, an inhibitor of haemostasis

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ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY 2001年第8期57卷 1071-1078页

作者： Huizinga, EG Schouten, A Connolly, TM Kroon, J Jan, JJA Gros, P Univ Utrecht Bijvoet Ctr Biomol Res Dept Crystal & Struct Chem NL-3584 CH Utrecht Netherlands Univ Utrecht Med Ctr Biomembrane Inst Dept HaematolThrombosis & Haemostasis Lab NL-3508 GA Utrecht Netherlands Merck Sharp & Dohme Res Labs Dept Biol Chem West Point PA 19486 USA

Leech anti-platelet protein (LAPP) from the leech Haementeria officinalis is a collagen-binding protein that inhibits the collagen-mediated adhesion of blood platelets. The crystal structure of recombinant LAPP has been determined using single isomorphous replacement with anomalous scattering combined with solvent flattening and threefold molecular averaging. The model of LAPP has been refined to 2.2 Angstrom resolution (R factor 21.5%;free R factor 24.0%). LAPP contains an 89-residue C-terminal domain consisting of a central six-stranded antiparallel beta -sheet flanked on one side by an alpha -helix and on the other side by two extended loops with little secondary structure. A 36-residue N-terminal region is not visible in the electron-density map. This region is rich in glycine and lacks hydrophobic residues. It probably does not have a compact globular fold, but instead has an extended conformation and is flexible. The crystal packing suggests that LAPP may form tightly interacting dimers. The fold of the C-terminal domain of LAPP closely resembles that of the N-domain of hepatocyte growth factor (HGF), which classifies LAPP as a PAN domain. However, no significant sequence homology exists between LAPP and other PAN domains. Common structural features between LAPP and the HGF N-domain include two disulfide bonds that link the alpha -helix to the central region of the protein and five residues with a conserved hydrophobic nature that are located in the core of the domain. These conserved structural features may be an important determinant of the PAN-domain type of fold.

关键词：氨基酸序列结合部位胶原/代谢结晶结晶学 X线止血/药物作用肝细胞生长因子/化学水蛭/化学模型分子分子序列数据蛋白质构象蛋白质结构三级唾液蛋白质类和肽类/化学唾液蛋白质类和肽类/代谢唾液蛋白质类和肽类/药理学序列同源性氨基酸动物人类

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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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垂体后叶素和催产素用于腹腔镜子宫肌瘤剔除术中的比较

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中国医师杂志 2007年第12期9卷 1715-1716页

作者：钱素敏于静河北省沧州市中心医院妇科河北沧州061000

目的探讨垂体后叶素在腹腔镜下子宫肌瘤剔除术中的止血作用。方法腹腔镜下对168例子宫肌瘤患者行子宫肌瘤剔除术，其中肌壁间肌瘤93例，无蒂浆膜下子宫肌瘤75例。分为垂体后叶组88例和催产素组80例，分别对手术时间、术中出血量等进行... 详细信息

目的探讨垂体后叶素在腹腔镜下子宫肌瘤剔除术中的止血作用。方法腹腔镜下对168例子宫肌瘤患者行子宫肌瘤剔除术，其中肌壁间肌瘤93例，无蒂浆膜下子宫肌瘤75例。分为垂体后叶组88例和催产素组80例，分别对手术时间、术中出血量等进行比较。结果168例手术均获成功，垂体后叶组平均出血量及平均手术时间与较催产素组比较差异有统计学意义（P〈0.05）。结论垂体后叶素较催产素有效减少了子宫肌瘤剔除术中的出血，并缩短了手术时间。垂体后叶素的应用是一种有效的止血方法。

关键词：垂体激素类,后叶/治疗应用催产素/治疗应用止血/药物作用腹腔镜检查子宫肿瘤/外科学平滑肌瘤/外科学

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Molecular mechanisms underlying alcohol-induced cardioprotection: Contribution of hemostatic components - Introduction to the symposium

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ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 1999年第6期23卷 1108-1110页

作者： Zakhari, S NIAAA Bethesda MD 20892 USA

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