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Diagnosis of venous thromboembolism - Step-by-step approach to a still lethal disease

POSTGRADUATE MEDICINE 2000年第1期108卷 175-180页

作者： Rubins, JB Rice, K Univ Minnesota Sch Med Minneapolis MN 55455 USA

Accuracy in the diagnosis of venous thrombophlebitis is often dependent on the degree of clinical suspicion before testing. In this article, the authors examine important risk factors for this often deadly disease and describe the invasive and noninvasive tests available. They also define the circumstances in which each procedure is appropriate.

关键词：算法血管造影术危险因素敏感性与特异性体层摄影术 X线计算机/方法静脉血栓形成/血液静脉血栓形成/诊断静脉血栓形成/病因学静脉血栓形成/超声检查通气与血流灌注比值人类

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Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions

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THROMBOSIS AND HAEMOSTASIS 1999年第5期81卷 680-683页

作者： Kamphuisen, PW Eikenboom, JCJ Vos, HL Pablo, R Sturk, A Bertina, RM Rosendaal, FR Leiden Univ Med Ctr Ctr Hemostasis & Thrombosis Res NL-2300 RC Leiden Netherlands Leiden Univ Med Ctr Dept Clin Epidemiol NL-2300 RC Leiden Netherlands Leiden Univ Med Ctr Dept Clin Chem NL-2300 RC Leiden Netherlands

Factor VIII activity (factor VIII:C) levels greater than or equal to 150 IU/dl are associated with a 5- to 6-fold increased risk of venous thrombosis compared to levels <100 IU/dl, and fibrinogen levels greater than or equal to 5.0 g/l increase the thrombosis risk 4-fold. These high levels are present in 25%, resp. 3% of the patients with a first episode of venous thrombosis. These findings were based on measurements after the thrombotic event, so the factor VU[I and fibrinogen levels in thrombosis patients may have been influenced by acute phase reactions or ongoing inflammatory responses. In the present study we measured plasma C-reactive protein (CRP) as a sensitive marker of an acute phase reaction in 474 thrombosis patients and 474 age- and sex-matched healthy controls, that were part of the Leiden Thrombophilia Study (LETS). Mean and median CRP levels were higher in thrombosis patients than in the controls, suggesting inflammation in some patients. CRP affected both factor Vm and fibrinogen levels, in patients and controls alike. After adjustment for the effect of CRP, high factor WI:C levels still increased the thrombosis risk 6-fold and high fibrinogen levels Lf-fold, which is for both very similar to the risk before correction for CRP levels. These results show that although systemic inflammation may be present in some of the patients, elevated levels of factor VIII:C and fibrinogen were in general not caused by acute phase reactions. This further supports a causal relationship between both high factor VIII:C and fibrinogen levels and venous thrombosis.

关键词：急相反应/血液因子Ⅷ/代谢纤维蛋白原/代谢危险因素静脉血栓形成/血液静脉血栓形成/病理生理学成年人老年人女(雌)性人类男(雄)性中年人

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Hormonal state rather than age influences cut-off values of protein S: Reevaluation of the thrombotic risk associated with protein S deficiency

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1093-1096页

作者： Liberti, G Bertina, RM Rosendaal, FR Leiden Univ Ctr Med Dept Hematol Hemostasis & Thrombosis Res Ctr Leiden Netherlands Univ Hosp Hematol & BMT Unit Palermo Italy Leiden Univ Med Ctr Dept Clin Epidemiol NL-2300 RA Leiden Netherlands

Of the well known risk factors for thrombosis protein S deficiency is one of the most difficult to diagnose with certainty, Reliable estimates for the prevalence of protein S deficiency in the general population are not available and the risk of thrombosis is a controversial issue. It has been shown that levels of protein S fluctuate over time. However the determinants of low levels of protein S in the healthy population are not clear. Therefore, we evaluated the influence of sex, age and hormonal state on the antigen levels of protein S in 474 healthy control subjects of the Leiden Thrombophilia Study (LETS). In univariate analysis, sex, age, oral contraceptive (OC) use and post-menopausal state all influenced protein S antigen levels. In a multivariate model for the whole sample only menopausal state and OC use had still an effect on the levels of total protein S and only menopausal state had an independent effect on the values of free protein S, On the basis of this analysis we established different cut-off levels for these subgroups and we re-evaluated in the Leiden Thrombophilia Study the risk of thrombosis for individuals with low protein S using these different reference ranges. With these specific cut-off points, we did not observe an increase in the risk of thrombosis in patients deficient of total protein S (OR 1.2, 95% CI 0.5-2.9) or free protein S (OR 1.3, 95% CI 0.5-3.5). When men and women were analyzed separately, the risk in women was 1.5 (95% CI 0.4-5.4) and 2.4 (95% CI 0.6-9.2) for total and free protein S deficiencies, respectively;and there was no increase in thrombotic risk for men. We conclude that it may be helpful to apply separate cut-off levels in the assessment of protein S levels This does not, however explain the differences between our results and those of others in the estimate of thrombotic risk of protein S deficiency.

关键词：病例对照研究避孕药口服/治疗应用性腺甾类激素/代谢绝经期/血液蛋白质S/代谢蛋白质S缺乏/血液蛋白质S缺乏/并发症参考值危险因素性征静脉血栓形成/血液静脉血栓形成/病因学青少年成年人老年人女(雌)性人类男(雄)性中年人

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Ruling out acute deep vein thrombosis by ELISA plasma D-dimer assay versus ultrasound in inpatients more than 70 years old

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ANGIOLOGY 1999年第11期50卷 873-882页

作者： Le Blanche, AF Siguret, V Settegrana, C Bohus, S de Chermont, EL Andreux, JP Gaussem, P Charles Foix Jean Rostand Univ Hosp Grp Dept Radiol & Med Imaging F-94205 Ivry France Charles Foix Jean Rostand Univ Hosp Grp Lab Haematol & Haemostasis Ivry France

In geriatric care, deep-vein thrombosis (DVT) is mostly diagnosed by noninvasive techniques. The objectives of this prospective study were: (1) to evaluate the power of ELISA plasma D-dimer assay versus ultrasound (US) in ruling out acute DVT of the lower limbs in symptomatic geriatric inpatients, and (2) to determine the most effective D-dimer cutoff value over the age of 70 years. Over a 10-month period, inpatients with suspected lower limb DVT simultaneously underwent US examination and ELISA plasma D-dimer assay. Noninclusion criteria were comorbid conditions able to modify the D-dimer level. Data were processed by receiver operating characteristic (ROC) curve analysis. In total, 150 patients (125 women, 25 men), average age 86.3 years (range 70-101) were included. A diagnosis of lower limb DVT was established in 53 patients (35.3%). With a 500 ng/mL D-dimer cutoff conventional value, DVT was ruled out in only five patients (3.3%), whereas a 750 ng/mL value ruled out DVT in 19 patients (12.7%) with a sensitivity of 98.1%, and a negative predictive value of 95.0%. The only false negative corresponded to a patient with a 15-mm thrombus in the distal calf. In inpatients above 70, an ELISA plasma D-dimer value smaller than 750 ng/mL is a rapid reliable noninvasive means to rule out lower limb DVT, if color flow Doppler ultrasound is not available on site.

关键词：酶联免疫吸附测定纤维蛋白纤维蛋白原降解物/分析试验预期值前瞻性研究 ROC曲线敏感性与特异性超声检查多普勒彩色静脉血栓形成/血液静脉血栓形成/诊断静脉血栓形成/超声检查老年人老年人 80以上女(雌)性人类男(雄)性

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Antithrombotic efficacy of thrombin inhibitor L-374,087: Intravenous activity in a primate model of venous thrombus extension and oral activity in a canine model of primary venous and coronary artery thrombosis

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 503-510页

作者： Cook, JJ Gardell, SJ Holahan, MA Sitko, GR Stump, GL Wallace, AA Gilberto, DB Hare, TR Krueger, JA Dyer, DL Sanderson, PEJ Vacca, JP Shafer, JA Lynch, JJ Merck Res Labs Dept Pharmacol W Point PA 19486 USA Merck Res Labs Dept Biol Chem W Point PA 19486 USA Merck Res Labs Dept Lab Anim Resources W Point PA 19486 USA Merck Res Labs Dept Med Chem W Point PA 19486 USA

The small molecule direct thrombin inhibitor L-374,087 was characterized across species in an in vitro activated partial thromboplastin clotting time (aPTT) assay and in vivo in rhesus monkey and dog thrombosis models. In vitro in rhesus, dog, and human plasma, L-374,087 concentrations eliciting 2-fold increases in aPTT were 0.25, 1.9, and 0.28 mu M, respectively. In anesthetized rhesus monkeys, 300 mu g/kg bolus plus 12 mu g/kg/ min and 300 mu g/kg bolus plus 30 mu g/kg/min L-374,087 i.v. infusions significantly reduced jugular vein thrombus extension, with both regimens limiting venous thrombus extension to 2-fold that of baseline thrombus mass compared with a 5-fold extension observed in the vehicle control group. Antithrombotic efficacy in the rhesus with the-lower-dose regimen was achieved with 2.3- to 2.4-fold increases in aPTT and prothrombin time. In a conscious instrumented dog model of electrolytic vessel injury, the oral administration of two 10 mg/kg L-374,087 doses 12 h apart significantly reduced jugular vein thrombus mass, reduced the incidence of and delayed time to occlusive coronary artery thrombosis, and significantly reduced coronary artery thrombus mass and ensuing posterolateral myocardial infarct size. Antithrombotic efficacy in the dog was achieved with 1.6- to 2.0-fold increases in aPTT at 1 to 6 h after oral dosing with L-374,087. These results indicate significant antithrombotic efficacy against both venous and coronary arterial thrombosis with L-374,087 with only moderate elevations in aPTT or prothrombin time. The oral efficacy of L-374,087 characterizes this compound as a prototype for the further development of orally active direct thrombin inhibitors.

关键词：投药口服麻醉出血时间血液凝固/药物作用冠状动脉血栓形成/血液冠状动脉血栓形成/药物疗法纤维蛋白溶解药/投药和剂量纤维蛋白溶解药/药代动力学纤维蛋白溶解药/药理学血细胞比容血红蛋白类/代谢注射静脉内颈静脉/病理学恒河猴部分促凝血酶原时间血小板计数/药物作用吡啶酮类/投药和剂量吡啶酮类/药代动力学吡啶酮类/药理学磺胺类/投药和剂量磺胺类/药代动力学磺胺类/药理学凝血酶/拮抗剂和抑制剂静脉血栓形成/血液静脉血栓形成/药物疗法动物狗女(雌)性人类男(雄)性

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Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1011-1014页

作者： Villa, P Aznar, J Vaya, A España, F Ferrando, F Mira, Y Estellés, A La Fe Univ Hosp Dept Clin Pathol Valencia 46009 Spain La Fe Univ Hosp Res Ctr Valencia 46009 Spain

Heparin cofactor II (HCII) is a specific inhibitor of thrombin in the presence of heparin or dermatan sulphate. Although there have been reports on families in which a heterozygous HCII deficiency is associated with thromboembolic events, several epidemiological studies revealed that heterozygous HCII deficiency is as prevalent among healthy subjects as it is among patients with deep venous thrombosis (DVT). It is therefore not yet clear whether HCII is or is not a thrombotic risk factor. We analyze and describe in an extended family the biochemical and genetic thrombophilic risk factors and evaluate the potential thrombotic risk involved in homozygous and heterozygous HCII deficiency, either alone or associated with other thrombotic or circumstantial risk factors. The propositus has had three episodes of DVT and a pulmonary embolism. During the first episode of DVT the patient was diagnosed as having AT deficiency. Later, a functional and antigenic HCII deficiency, compatible with the homozygous form, was detected. The family study shows that both the propositus and her sister have homozygous HCII deficiency and that 12 of the 27 family members have heterozygous HCII deficiency. This is possibly the first case report on a homozygous phenotype for the HCII deficiency with, in addition, partial AT deficiency. The propositus has suffered several thrombotic events, unlike the other 12 family members with heterozygous HCII deficiency and her sister, who is also homozygous for this disorder. We suggest that HCII deficiency may play a limited in vivo role as a thrombotic risk factor unless associated with AT deficiency or another congenital thrombotic risk factor.

关键词：抗凝药/治疗应用纤维蛋白/缺乏肝素辅助因子Ⅱ/缺乏杂合子纯合子系谱表型妊娠并发症血液/血液妊娠并发症血液/药物疗法肺栓塞/血液肺栓塞/遗传学危险因素静脉血栓形成/血液静脉血栓形成/并发症静脉血栓形成/遗传学青少年成年人儿童儿童学龄前女(雌)性人类婴儿男(雄)性中年人妊娠

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Comparison of diagnostic performance of three new fast D-Dimer assays in the exclusion of deep vein thrombosis

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CLINICAL CHEMISTRY 2000年第2期46卷 286-287页

作者： Sadouk, M Desmarais, S Patenaude, JV Lepage, R Univ Montreal Ctr Hosp Hop St Luc Dept Biochem Montreal PQ H2X 3J4 Canada Univ Montreal Ctr Hosp Hop St Luc Dept Internal Med Montreal PQ H2X 3J4 Canada

D-Dimer (DD), a soluble cross-linked fibrin degradation product, has been suggested as a reliable marker to rule out deep vein thrombosis (DVT) (1)(2)(3)(4). The disease can be ruled out in approximately one-third of outpatients suspected with DVT when the plasma concentration of DD is below an appropriate cutoff value (4). Measurement of plasma DD concentrations has been performed by two major methods: ELISA, which is highly sensitive but time-consuming; and latex agglutination, which is faster but less sensitive than ELISA (2)(4). SimpliRED, a latex assay, detects DD directly in whole blood, avoiding the plasma preparation step (5). However, this assay gives only qualitative results and adds an interindividual observation bias that may partly explain the discordant sensitivity values obtained by different investigators (3)(5)(6)(7). In the present study, we investigated the clinical utility of three new fast DD assays in the diagnosis of DVT.

关键词：酶联免疫吸附测定纤维蛋白纤维蛋白原降解物/分析散射测浊法和比浊法敏感性与特异性静脉血栓形成/血液静脉血栓形成/诊断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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Venous thrombosis, oral contraceptives and high factor VIII levels

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1024-1027页

作者： Bloemenkamp, KWM Helmerhorst, FM Rosendaal, FR Vandenbroucke, JP Leiden Univ Med Ctr Dept Clin Epidemiol NL-2300 RC Leiden Netherlands Leiden Univ Med Ctr Thrombosis & Hemostasis Res Ctr NL-2300 RC Leiden Netherlands Leiden Univ Med Ctr Dept Obstet Gynaecol & Reprod Med NL-2300 RC Leiden Netherlands

Recently, it has been described that elevated plasma levels of factor VIII are a strong risk factor for venous thrombosis. We analysed the data of the Leiden Thrombophilia Study, a population based case-control study on the causes of venous thrombosis, to verify whether the risk due to oral contraceptive use was higher in women with higher factor Vm levels. Furthermore we investigated the joint risk of high factor VIII levels and oral contraceptive use. We selected 155 premenopausal women with deep-vein thrombosis and 169 control subjects, aged 15-49, who were at the time of their thrombosis (or similar date in control) not pregnant, nor in the puerperium, did not have a recent miscarriage, and were not using injectable progestogens. Of the patients, 109 (70%) women had used oral contraceptives during the month preceding their deep-vein thrombosis. in contrast to 65 (38%) of the control subjects (index date), yielding an odds ratio for oral contraceptive use of 3.8 (95% CI 2.4-6.0). Of the women who suffered a deep-vein thrombosis 56 (36%) had high factor VIII levels (greater than or equal to 150 IU/dl) as compared with 29 (17%) of the control subjects, yielding an odds ratio for high factor VIII of 4.0 (95% CI 2.0-8.0), relative to factor VIII levels <100 IU/dl. The joint effect of oral contraceptive use and high factor WI resulted in an odds ratio of 10.3 (95% CI 3.7-28.9), comparing women who had both with women who had neither. We conclude that then is an increase in risk due to oral contraceptive use in women with higher factor VIII levels and that both factors have additive effects.

关键词：病例对照研究因子Ⅷ/代谢 Logistic模型比值比危险因素静脉血栓形成/血液静脉血栓形成/化学诱导静脉血栓形成/病因学青少年成年人女(雌)性人类中年人

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Low levels of heparin-releasable tissue factor pathway inhibitor in young patients with thrombosis

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THROMBOSIS AND HAEMOSTASIS 1999年第2期81卷 203-207页

作者： Ariëns, RAS Alberio, G Moia, M Mannucci, PM IRCCS Osped Maggiore Angelo Bianchi Bonomi Hemophilia & Thrombosis Ctr Milan Italy Univ Milan Milan Italy

An association between deficiency of tissue factor pathway inhibitor (TFPI) and thrombosis has not been clearly demonstrated in humans, but previous studies have focused on the measurement of plasma TFPI, which is only a small part of the total body TFPI. The major fraction of this natural anticoagulant can be measured in plasma after release by heparin injection. To investigate if deficiency of heparin-releasable TFPI is associated with thrombosis, we measured TFPI activity in plasma before and 10 min after intravenous injection of 7500 IU unfractionated heparin in 64 young patients with venous thrombosis, 49 young patients with arterial thrombosis and 38 healthy individuals. Post-heparin TFPI activity levels were significantly lower in the group of patients with venous thrombosis than in controls (mean +/- SD: 230% +/- 39 vs 260% +/- 34, p = 0.0002), whereas there was no difference for patients with arterial thrombosis. Defining the normal range as the mean +/- 2 SD of TFPI activity in controls, twelve patients had low post-heparin TFPI activity levels, seven with venous and five with arterial thrombosis. Low levels of TFPI activity were confirmed by immunoassay in six of the seven patients with venous thrombosis and two of the five patients with arterial thrombosis, and were present also in at least one first degree relative of six patients, suggesting that the defect might be inheritable. However, the causative role of low heparin-releasable TFPI remains uncertain, because co-segregation of the defect with thrombotic symptoms could not be demonstrated in the small number of families studied.

关键词：年龄因素动脉闭塞性疾病/血液动脉闭塞性疾病/病因学因子Ⅹa/拮抗剂和抑制剂肝素/药理学颅内栓塞和血栓形成/血液颅内栓塞和血栓形成/病因学脂蛋白类/血液脂蛋白类/缺乏系谱血栓形成倾向/血液血栓形成倾向/病因学血栓形成倾向/遗传学血栓形成/血液血栓形成/病因学静脉血栓形成/血液静脉血栓形成/病因学青少年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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RPR120844, a novel, specific inhibitor of coagulation factor Xa inhibits venous thrombosis in the rabbit

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THROMBOSIS AND HAEMOSTASIS 1999年第1期81卷 157-160页

作者： Bostwick, JS Bentley, R Morgan, S Brown, K Chu, V Ewing, WR Spada, AP Pauls, H Perrone, MH Dunwiddie, CT Leadley, RJ Rhone Poulenc Rorer Res & Dev Cardiovasc Drug Discovery Collegeville PA 19426 USA

The in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TMI measured at the end of a 50 min infusion, was significantly reduced (p < 0.05 vs saline-treated animals) by RPR120844 at 30 and 100 mu g/kg/min. At doses of 10, 30 and 100 mu g/kg/min: APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 +/- 0.3, 1.5 +/- 0.9 and 2.4 +/- 0.6 mu M, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment Values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

关键词：剂量效应关系药物因子Ⅹa/拮抗剂和抑制剂纤维蛋白溶解药/化学纤维蛋白溶解药/药理学部分促凝血酶原时间磺胺类/化学磺胺类/药理学噻吩类/化学噻吩类/药理学静脉血栓形成/血液静脉血栓形成/药物疗法动物兔

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