Antibodies to tissue-type plasminogen activator (t-PA) in patients with inflammatory bowel disease: high prevalence, interactions with functional domains of t-PA and possible implications in thrombosis

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased prevalence of thromboembolic events. The pathogenetic mechanisms of these events include reduced fibrinolysis, which may be caused by antibodies to tissue-type plasminogen activator (t-PA). OBJECTIVES: To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics. PATIENTS AND METHODS: We immunoenzymatically measured anti-t-PA antibodies in plasma from 97 consecutive IBD patients and 97 age- and sex-matched healthy controls. We also assessed the antibody interactions with different epitopes of t-PA, the antibody inhibition on t-PA activity and the correlations with clinical features and other serum antibodies. RESULTS: IBD patients had higher median anti-t-PA antibody levels (5.4 U mL(-1) vs. 4.0 U mL(-1); P < 0.0001): 18 patients were above the 95th percentile of the controls (OR 5.3; 95% CI 1.7-16.3; P < 0.003), and the six with a history of thrombosis tended to have high levels (6.9 U mL(-1)). Anti-t-PA antibody levels did not correlate with IBD type, activity, location or treatment, or with age, sex, acute-phase reactants or other antibodies. The anti-t-PA antibodies were frequently IgG1 and bound t-PA in fluid phase; they recognized the catalytic domain in 10 patients and the kringle-2 domain in six. The IgG fraction from the three patients with the highest anti-t-PA levels slightly reduced t-PA activity in vitro. CONCLUSIONS: The prevalence of anti-t-PA antibodies is high in IBD patients. By binding the catalytic or kringle-2 domains of t-PA, these antibodies could lead to hypofibrinolysis and contribute to the prothrombotic state of IBD.     

Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator

The nature of the enhanced blood fibrinolytic activity which is known to occur during cardiopulmonary bypass is not understood. We show here that the cause is an increase in extrinsic (tissue-type) plasminogen activator. In six patients, the nature of the enhanced blood fibrinolytic activity that evolved during cardiopulmonary bypass was characterized by differential inhibition using the fibrin plate method and was shown to be C1-inactivator-resistant (extrinsic-activator activity). The C1-inactivator-resistant-activator activity was completely quenched by an antibody against extrinsic (tissue-type) plasminogen activator but not by antiurokinase, proving that the activity was due to the presence of extrinsic (tissue-type) plasminogen activator. The concentration of extrinsic (tissue-type) plasminogen activator increased during cardiopulmonary bypass and disappeared rapidly thereafter. Fibrinogen, plasminogen and alpha 2-antiplasmin were not consumed during cardiopulmonary bypass, while no increase or occasionally a moderate one in fibrinogen degradation products occurred. This is in accord with the property of extrinsic (tissue-type) plasminogen activator which activates plasminogen predominantly at sites where fibrin is present and not in the free circulation.     

重组组织型纤溶酶原激活剂静脉溶栓治疗急性心肌梗死后的QT离散度变化

３６例急性心肌梗死患者接受重组组织型纤溶酶原激活剂（ｒｔ－ＰＡ）静脉溶栓治疗。其中有效２１例，无效１３例。有效组在溶栓后２小时、８小时、２４小时的ＱＴｃ离散度（ＱＴｃｄ）与溶栓前相比较，有下降趋势，但未达到统计显著性。无效组在溶栓后２小时、８小时、２４小时的ＱＴｃｄ与溶栓前相比较，有显著性延长（Ｐ＜０００１）。有效组与无效组相比，溶栓后２小时、８小时、２４小时之ＱＴｃｄ，差异有显著性（Ｐ＜０００１）。     

Cost-Effectiveness of Magnetic Resonance Imaging-Guided Thrombolysis for Patients With Stroke With Unknown Time of Onset

ObjectivesPatients waking up with stroke symptoms are often excluded from intravenous thrombolysis with alteplase (IV-tpa). The WAKE-UP trial, a European multicenter randomized controlled trial, proved the clinical effectiveness of magnetic resonance imaging-guided IV-tpa for these patients. This analysis aimed to assess the cost-effectiveness of the intervention compared to placebo.MethodsA Markov model was designed to analyze the cost-effectiveness over a 25-year time horizon. The model consisted of an inpatient acute care phase and a rest-of-life phase. Health states were defined by the modified Rankin Scale (mRS). Initial transition probabilities to mRS scores were based on WAKE-UP data and health state utilities on literature search. Costs were based on data from the University Medical Center Hamburg-Eppendorf, literature, and expert opinion. Incremental costs and effects over the patients’ lifetime were estimated. The analysis was conducted from a formal German healthcare perspective. Univariate and probabilistic sensitivity analyses were performed.ResultsTreatment with IV-tpa resulted in cost savings of €51 009 and 1.30 incremental gains in quality-adjusted life-years at a 5% discount rate. Univariate sensitivity analysis revealed incremental cost-effectiveness ratio being sensitive to the relative risk of favorable outcome on mRS for placebo patients after stroke, the costs of long-term care for patients with mRS 4, and patient age at initial stroke event. In all cases, IV-tpa remained cost-effective. Probabilistic sensitivity analysis proved IV-tpa cost-effective in >95% of the simulations results.ConclusionsMagnetic resonance imaging-guided IV-tpa compared to placebo is cost-effective in patients with ischemic stroke with unknown time of onset.     

An Experimental Study on the Flexibility of Prevention against Thrombosis Following Mechanical Valve Replacement by tPA Gene Transduction

Objectives Use a gene suture immersed recombinant tissue-type plasminogen activator （r-tPA）expression plasmid to transduce myocardia to prevent the thrombosis after mechanical tricuspid valve replacement in pigs. Methods A r-tPA gene plasmid was constructed and conjugated to a novel cationic phosphonolipid and a r-tPA gene suture was made. Eighteen pigs were selected and divided into two groups at randomization. There were 9 pigs in the experimental group and 9 in the control group, all the 18 pigs＇ tricuspids were replaced with mechanical valves. The gene threads were sutured into the right ventricular walls near mechanical valves and an ultrasound was used on the surfaces of the right ventricular walls for the gene transfer in the experimental group. Coagulative function, D-dimer level of the blood and the thrombosis on the surfaces of the valves were observed. Results r-tPA gene plasmid was successfully constructed and r-tPA protein was expressed in the ventricular cells around the gene sutures. D-dimer reached its peak level （ 1.67 ±0. 79） μg · mL^-1 in 1 week after operation in two groups, but it decreased to preoperation level thereafter in control group and kept on the high level and reincreased to a new high level （ 1.89 ± 0.79 ） μg · mL^-1 until the end of the experiment in experimental group. The thromboses around the valves were found in all the control group （100%） but only 1 （ 11.11% ） case in experimental group. There were no changes in prothrombin time pre and post operation in two groups. Conclusions Using gene suture immersed r-tPA expression plasmid to transduce myocardia might be a best substitution for life long anti-coagulation therapy for the patients, who underwent operation.     

Changes in hemostatic and fibrinolytic proteins in patients receiving L-asparaginase therapy

Hemostatic changes were evaluated in ten patients with acute lymphoblastic leukemia and lymphoma who received chemotherapy with L-asparaginase, vincristine, and prednisolone for 1 week. Following treatment, prothrombin time and activated partial thromboplastin time were significantly prolonged, while a marked decrease in fibrinogen levels was observed. The values for cross-linked fibrin degradation products, however, remained within normal limits during treatment, which excluded the possibility of disseminated intravascular coagulation. The concentrations of coagulation inhibitors (antithrombin III, protein C, and protein S), plasminogen, and alpha 2 antiplasmin also significantly decreased; however, levels of both tissue-type plasminogen activator and plasminogen activator inhibitor, which are synthesized in endothelial cells, increased during the treatment. Although a decrease was observed in concentrations of many coagulation factors, including subunits A and B of factor XIII, the activity and antigenicity of factor VII significantly increased following the treatment. From this study, we concluded that these hemostatic abnormalities caused by the administration of L-asparaginase produced a labile condition that easily inclines to bleeding or thrombosis.     

急性脑梗死合并2型糖尿病患者超早期rt-PA静脉溶栓的效果分析

目的 重组组织型纤溶酶原激活剂（rt-PA）静脉溶栓治疗急性脑梗死合并2型糖尿病患者的疗效.方法 回顾性分析70例急性脑梗死合并2型糖尿病患者的临床资料,其中rt-PA静脉溶栓组31例,单纯治疗组39例.对患者行NIHSS评分,改良Rankin（MRS）评分及Barthel指数评估早期及晚期预后.结果 静脉溶栓组24 h时NIHSS评分较单纯治疗组低（P＜0.05）;静脉溶栓组7d时NIHSS评分与单纯治疗组无明显差异（P＞0.05）;静脉溶栓组90 d时MRS评分显示预后良好的患者较单纯治疗组多（P＜0.05）;静脉溶栓组90 d时Barthel指数较单纯治疗组升高（P＜0.05）.静脉溶栓组出血事件较单纯治疗组高（P＜0.05）;但静脉溶栓组症状性脑出血与单纯治疗组相比无显著差异（P＞0.05）.结论 经rt-PA静脉溶栓治疗急性脑梗死合并2型糖尿病患者的总体疗效优于传统单纯综合治疗,但仍需注意静脉溶栓后出血性事件的发生.     

早期r-tpA溶栓治疗急性脑梗死的护理

目的:探讨重组组织型纤溶酶原激活物静脉溶栓治疗急性脑梗死的疗效与护理方法。方法:对符合适应证的48例脑梗死患者给予重组组织型纤溶酶原激活物静脉溶栓治疗。观察患者疗效。结果:基本治愈42例,显著进步3例,进步2例,无效1例。出现皮肤黏膜出血2例,血尿1例,黑便1例。结论:在溶栓过程中严密观察病情,特别是在溶栓中及溶栓后24 h内对出血倾向、血压、意识水平、肌力的观察,预防及处理并发症,能够为患者更好的恢复起重要的作用。     

Projected Cost-Effectiveness of Primary Angioplasty for Acute Myocardial Infarction

Objectives. This study sought to evaluate the cost-effectiveness of primary angioplasty for acute myocardial infarction under varying assumptions about effectiveness, existing facilities and staffing and volume of services.

Background. Primary angioplasty for acute myocardial infarction has reduced mortality in some studies, but its actual effectiveness may vary, and most U.S. hospitals do not have cardiac catheterization laboratories. Projections of cost-effectiveness in various settings are needed for decisions about adoption.

Methods. We created a decision analytic model to compare three policies: primary angioplasty, intravenous thrombolysis and no intervention. Probabilities of health outcomes were taken from randomized trials (base case efficacy assumptions) and community-based studies (effectiveness assumptions). The base case analysis assumed that a hospital with an existing laboratory with night/weekend staffing coverage admitted 200 patients with a myocardial infarction annually. In alternative scenarios, a new laboratory was built, and its capacity for elective procedures was either 1) needed or 2) redundant with existing laboratories.

Results. Under base case efficacy assumptions, primary angioplasty resulted in cost savings compared with thrombolysis and had a cost of $12,000/quality-adjusted life-year (QALY) saved compared with no intervention. In sensitivity analyses, when there was an existing cardiac catheterization laboratory at a hospital with ≥200 patients with a myocardial infarction annually, primary angioplasty had a cost of <$30,000/QALY saved under a wide range of assumptions. However, the cost/QALY saved increased sharply under effectiveness assumptions when the hospital had <150 patients with a myocardial infarction annually or when a redundant laboratory was built.

Conclusions. At hospitals with an existing cardiac catheterization laboratory, primary angioplasty for acute myocardial infarction would be cost-effective relative to other medical interventions under a wide range of assumptions. The procedure’s relative cost-ineffectiveness at low volumes or redundant laboratories supports regionalization of cardiac services in urban areas. However, approaches to overcoming competitive barriers and close monitoring of outcomes and costs will be needed.