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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 73 records · Page 4Linked to original sources
PubMed1999

Thrombosis and anticoagulation.

Most of the major advances in thrombosis research have occurred in the last 50 years, reflecting progress in biomedical sciences and clinical trials methodology. Improved understanding of the mechanisms of thrombogenesis has led to the discovery of a plethora of new antithrombotic agents that target many of the key steps in blood coagulation and platelet activation. Although most of these compounds are still under development, low-molecular-weight heparins (LMWH), glycoprotein (GP) IIb/IIIa receptor antagonists, and inhibitors of the adenosine diphosphate (ADP) receptor on platelets have already established their niche in the clinic. The vessel wall has emerged as a major player, both in protecting against and in promoting thrombosis, and as we approach the new millennium, compounds are being developed that have the potential to prevent and treat thrombosis by modulating vessel wall function.

Anticoagulants↗
PubMed1998

Use of a clinical model for safe management of patients with suspected pulmonary embolism.

BACKGROUND: The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. OBJECTIVE: To determine the safety of a clinical model for patients with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Five tertiary care hospitals. PATIENTS: 1239 inpatients and outpatients with suspected pulmonary embolism. INTERVENTIONS: A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. MEASUREMENTS: Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. RESULTS: Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). CONCLUSION: Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.

Algorithms↗
PubMed1998

Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism.

BACKGROUND: Patients with suspected pulmonary embolism often have nondiagnostic lung scans and may present in circumstances where lung scanning is unavailable. Levels of D-dimer, a fibrin-specific product, are increased in patients with acute thrombosis; this may simplify the diagnosis of pulmonary embolism. OBJECTIVE: To determine the sensitivity and specificity of a whole-blood D-dimer assay in patients with suspected pulmonary embolism and in subgroups of patients with low pretest probability of pulmonary embolism or nondiagnostic lung scans. DESIGN: Prospective cohort. SETTING: Four tertiary care hospitals. PATIENTS: 1177 consecutive patients with suspected pulmonary embolism. MEASUREMENTS: All patients underwent an assessment of pretest probability by use of a standardized clinical model, a D-dimer assay, ventilation-perfusion lung scanning, and bilateral compression ultrasonography. Patients in whom pulmonary embolism was not initially diagnosed were followed for 3 months. Accordingly, patients were categorized as positive or negative for pulmonary embolism. RESULTS: Of the 1177 patients, 197 (17%) were classified as positive for pulmonary embolism. Overall, the D-dimer assay showed a sensitivity of 84.8% and a specificity of 68.4%. In 703 patients (3.4%) with a low pretest probability of pulmonary embolism, the likelihood ratio associated with a negative D-dimer test result was 0.27, resulting in a posterior probability of 1.0% (95% CI, 0.3% to 2.2%). In 698 patients with nondiagnostic lung scans (previous probability, 7.4%), the likelihood ratio associated with a negative D-dimer test result was 0.36, resulting in a posterior probability of 2.8% (CI, 1.4% to 4.8%). CONCLUSIONS: A normal D-dimer test result is useful in excluding pulmonary embolism in patients with a low pretest probability of pulmonary embolism or a nondiagnostic lung scan.

Algorithms↗
PubMed1998

The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.

This paper describes the role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Inability to compress the common femoral or popliteal vein is usually diagnostic of a first episode of deep venous thrombosis in symptomatic patients (positive predictive value of about 97%). Full compressibility of both of these sites excludes proximal deep venous thrombosis in symptomatic patients (negative predictive value of about 98%). In patients with suspected deep venous thrombosis or in those who present with suspected pulmonary embolism but have a nondiagnostic lung scan, the subsequent risk for symptomatic venous thromboembolism is very low (<2% during 6 months of follow-up) provided that ultrasonography of the proximal veins remains normal in the course of 1 week (suspected deep venous thrombosis) or 2 weeks (suspected pulmonary embolism). Anticoagulation and further diagnostic testing can usually be safely withheld in these situations. Venous ultrasonography is much less reliable for the diagnosis of asymptomatic, isolated distal, and recurrent deep venous thrombosis than for the diagnosis of a first episode of proximal deep venous thrombosis in symptomatic patients. Clinical evaluation of the probability of deep venous thrombosis or pulmonary embolism, preferably by using a validated clinical model, complements venous ultrasonographic findings and helps to identify patients who would benefit from additional (often invasive) diagnostic testing. Thus, venous ultrasonography is thought to be a very valuable test for the diagnosis and management of patients with suspected deep venous thrombosis or pulmonary embolism.

Humans↗
PubMed1998

Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin.

BACKGROUND: Low-molecular-weight (LMW) heparins are safe and effective for out-of-hospital treatment of acute deep-vein thrombosis (DVT) in a clinical trial setting. We examined the efficacy, safety, and feasibility of home treatment with LMW heparin of consecutive eligible patients with acute DVT in a routine care setting. In addition, we report our experience with patient compliance, acceptance, and satisfaction. METHODS: We performed a prospective cohort study of consecutive patients presenting to 2 thromboembolism clinics in a large Ontario city. Eligible patients were treated with LMW heparin for a minimum of 5 days and with long-term warfarin sodium. Outcomes included the incidences of bleeding and recurrence of DVT and pulmonary embolism and patient satisfaction as determined by a questionnaire. RESULTS: One hundred thirteen patients with objectively confirmed DVT underwent screening; 89 patients were treated at home with LMW heparin. During the study, 1 patient died of a combination of pulmonary embolism and major bleeding, another patient required admission to the hospital for bleeding, and 5 patients with active malignant disease had recurrent DVT. Of the patients who completed the satisfaction questionnaire, 75 (91%) of 82 were pleased with home treatment; 44 (70%) of 63 felt comfortable self-injecting the LMW heparin; and 71 (92%) of 77 were satisfied with the support and instruction they received during the outpatient treatment. CONCLUSIONS: Outpatient treatment of DVT with LMW heparin is safe, effective, and feasible for most patients and is associated with a high degree of patient satisfaction.

Adult↗
PubMed1998

Characterization of the stress-inducing effects of homocysteine.

The mechanism by which homocysteine causes endothelial cell (EC) injury and/or dysfunction is not fully understood. To examine the stress-inducing effects of homocysteine on ECs, mRNA differential display and cDNA microarrays were used to evaluate changes in gene expression in cultured human umbilical-vein endothelial cells (HUVEC) exposed to homocysteine. Here we show that homocysteine increases the expression of GRP78 and GADD153, stress-response genes induced by agents or conditions that adversely affect the function of the endoplasmic reticulum (ER). Induction of GRP78 was specific for homocysteine because other thiol-containing amino acids, heat shock or H2O2 did not appreciably increase GRP78 mRNA levels. Homocysteine failed to elicit an oxidative stress response in HUVEC because it had no effect on the expression of heat shock proteins (HSPs) including HSP70, nor did it activate heat shock transcription factor 1. Furthermore homocysteine blocked the H2O2-induced expression of HSP70. In support of our findings in vitro, steady-state mRNA levels of GRP78, but not HSP70, were elevated in the livers of cystathionine beta-synthase-deficient mice with hyperhomocysteinaemia. These studies indicate that the activation of stress response genes by homocysteine involves reductive stress leading to altered ER function and is in contrast with that of most other EC perturbants. The observation that homocysteine also decreases the expression of the antioxidant enzymes glutathione peroxidase and natural killer-enhancing factor B suggests that homocysteine could potentially enhance the cytotoxic effect of agents or conditions known to cause oxidative stress.

Animals↗
PubMed1998

The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study of patients who underwent hip or knee arthroplasty. Canadian Collaborative Group.

BACKGROUND: Despite low molecular weight heparin prophylaxis, the incidence of venographically detected, residual deep vein thrombosis after hip and knee arthroplasty remains high, at approximately 15% and 30%, respectively. Most of these thrombi are asymptomatic and of unknown clinical significance. Nevertheless, because they have the potential to grow, limiting prophylaxis to the in-hospital period may provide inadequate protection. METHODS: We studied a cohort of 1984 consecutive patients who had hip or knee arthroplasty at 1 of 28 participating hospitals. Patients received enoxaparin prophylaxis, 30 mg subcutaneously every 12 hours for up to 14 days, and underwent predischarge compression ultrasonography. Study end points were symptomatic deep vein thrombosis or pulmonary embolism during and after prophylaxis, asymptomatic venous thrombosis detected by predischarge compression ultrasonography, and major hemorrhage. The duration of follow-up was 84 days. RESULTS: Enoxaparin treatment was started a mean (+/- SD) of 17.9 +/- 10.4 hours after the completion of surgery and was given for a mean of 18.0 +/- 6.9 doses. Eighty-two patients (4.1%; 95% confidence interval, 3.3%-5.0%) developed venous thromboembolism. The rates of thromboembolic events during and after prophylaxis were 2.1% and 2.0%, respectively. Only 3 patients (0.15%) had abnormal predischarge compression ultrasonography. Three patients (0.15%) died of pulmonary embolism. Major hemorrhage occurred in 58 patients (2.9%; 95% confidence interval, 2.2%-3.7%). CONCLUSIONS: Postoperative prophylaxis with enoxaparin for a mean of 9 days is associated with a clinically acceptable rate of symptomatic venous thromboembolism and major hemorrhage. Predischarge compression ultrasonography cannot be justified.

Adult↗
PubMed1998

Stereotypic behavioral responses to free-base cocaine and the development of behavioral sensitization in Drosophila.

Cocaine abuse is a large social and economic problem that has received much public and scientific attention in recent years. Rodent and primate models have been used to study the behavioral and neurological effects of cocaine. Repeated intermittent doses of cocaine lead to progressive increases in both locomotor activity and stereotyped behaviors known as 'reverse tolerance' or behavioral sensitization, which may model the behavioral and neurochemical processes occurring in cocaine-addicted humans [1]. The biological basis of sensitization is poorly understood. We report that free-base cocaine administered in volatile form to the fruit fly Drosophila melanogaster induces multiple reflexive motor responses that resemble cocaine-induced behaviors in rodents. These behaviors are both dose dependent and sexually dimorphic. Furthermore, Drosophila develops a behavioral sensitization to intermittent doses of cocaine. These results suggest that the pathways leading to cocaine-induced responses and sensitization are evolutionarily conserved between Drosophila and higher vertebrates, and that this genetically tractable animal can be used as a new model system to help determine the biological mechanisms underlying these processes.

Animals↗
PubMed1998

Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: results of GUSTO-I. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries.

BACKGROUND: The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods. METHODS AND RESULTS: Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke. CONCLUSIONS: This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis.

Aged↗
PubMed1998

Hirudin causes more bleeding than heparin in a rabbit ear bleeding model.

This study was undertaken to determine the appropriateness of the current practice of using the activated partial thromboplastin time (APTT) to select hirudin doses. A rabbit bleeding ear model was used to compare the effects of various doses of heparin and hirudin on the relationship between the APTT and bleeding. In addition, the effects of these agents on the thrombin clotting time (TCT) and factor Xa clotting time also were examined. Both heparin and hirudin produced a concentration-dependent increase in bleeding. When bleeding was plotted as a function of APTT ratio, even a small increase in APTT ratio within the therapeutic range of 1.5 to 2.5 resulted in a marked increase in bleeding with hirudin but not with heparin. The TCT was more responsive than the APTT or factor Xa clotting time to increases in hirudin-induced bleeding. In this model, hirudin produces more bleeding than heparin when the agents are used in doses that increase the APTT ratio to the same extent. These studies highlight the pitfalls of extrapolating from experience with heparin when choosing a test to monitor new antithrombotics. Our findings also suggest that the TCT may be more responsive than the APTT for monitoring hirudin therapy.

Animals↗
PubMed1998

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators.

OBJECTIVES: We sought to show that hirudin might interact differently with streptokinase (SK) and tissue-type plasminogen activator (t-PA), which could reduce the incidence of death or reinfarction at 30 days. BACKGROUND: In a large-scale trial of patients with acute coronary syndromes, hirudin provided modest benefit compared with heparin. However, the interaction with thrombolytic agents was not specifically assessed. METHODS: Patients with symptoms of acute myocardial infarction and electrocardiographic ST segment elevation were treated with thrombolytic therapy and randomly assigned to receive hirudin or heparin. RESULTS: A total of 2,274 patients received t-PA, and 1,015 received SK. Baseline characteristics were balanced by antithrombin assignment. Among SK-treated patients, death or reinfarction at 30 days occurred more often in those treated with adjunctive heparin (14.4%) rather than hirudin (8.6%, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.20 to 2.66, p = 0.004). Among t-PA-treated patients, the rates were 10.9% with heparin and 10.3% with hirudin (OR 1.06, 95% CI 0.81 to 1.38, p = 0.68; for treatment heterogeneity: chi-square 4.20, degrees of freedom [df] 1, p = 0.04). After adjustment for baseline differences between thrombolytic groups, the rates were 9.1% for SK with hirudin, 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and 14.9% for SK with heparin (for treatment heterogeneity: chi-square 4.5, df 1, p = 0.03), suggesting that the beneficial treatment effect of hirudin was limited to the SK-treated patients. CONCLUSIONS: Hirudin interacts favorably with SK but not t-PA, highlighting the importance of thrombin activity after SK therapy and the potential for simulating the effects of a more potent fibrinolytic agent through direct antithrombin therapy.

Aged↗
PubMed1998

A simple clinical model for the diagnosis of deep-vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process.

OBJECTIVES: We recently demonstrated the utility of a clinical model combined with ultrasonography to assist the diagnostic approach in patients with suspected deep-vein thrombosis (DVT). In this study we also sought to demonstrate that the model is useful with impedance plethysmography, a less accurate and less utilized diagnostic test. The original clinical model is slightly cumbersome to use; thus at the completion of the study we attempted to develop a simpler scoring system with a goal of maintaining accuracy. DESIGN: An open, nonrandomized, multicentre trial. SETTING: Three centres, two in Canada, and one in Italy. SUBJECTS: Ambulatory patients with suspected deep-vein thrombosis. INTERVENTIONS: All patients were assessed clinically to determine the probability for deep-vein thrombosis prior to performing impedance plethysmography and venography. We compared the accuracy of impedance plethysmography between the three pretest probability categories of high, moderate and low. All of the above were performed and interpreted by independent observers. When the study was completed, we revised the clinical model by first performing a simple regression analysis then a multiple logistic regression analysis; a scoring system was devised using the latter. RESULTS: Impedance plethysmography is significantly more sensitive and less specific for all DVT in patients with high pretest probability for deep-vein thrombosis (P = 0.001). The post- test probability (positive predictive value) for deep-vein thrombosis with an abnormal impedance plethysmography result was significantly different (P = 0.0001) between the three pretest probability categories. Multiple regression analysis has provided a new model with only nine variables and a simple scoring system. The retrospective application of the revised clinical model, which is simpler to use, suggests it will provide similar results as the original clinical model when combined with impedance plethysmography. The combination of impedance plethysmography and the clinical model suggests patients are likely to have false positive results if they have a low or moderate pretest probability for deep-vein thrombosis and false negative results if the pretest probability is high. The combination of a low pretest probability and a normal impedance plethysmography result may exclude the need for serial testing, and represented more than 50% of our patient population. CONCLUSIONS: The use of the clinical model in conjunction with impedance plethysmography would decrease the number of false positive and negative diagnoses and could markedly decrease the need for serial impedance plethysmography. Combining the clinical model with impedance plethysmography could overcome the fact that impedance plethysmography is clearly less accurate than venous ultrasound imaging. The use of the revised clinical model may increase acceptability and utility, but prospective testing is required before widespread use.

Diagnosis, Differential↗
PubMed1998

Low-molecular-weight heparin for the treatment of venous thromboembolism.

Unfractionated heparin (UFH) binds to several plasma, platelet, and endothelial proteins, producing a highly variable anticoagulant response. For this reason, frequent anticoagulation monitoring and dosage adjustment are necessary during UFH administration. In contrast, low-molecular-weight heparins (LMWHs) exhibit less protein binding and provide more predictable anticoagulation with reduced need for patient monitoring and dosage adjustment. Therefore, LMWHs are potentially useful for anticoagulation therapy on an outpatient basis. Several recent clinical trials have compared LMWHs (administered primarily on an outpatient basis) and UFH for the treatment of venous thromboembolism. These trials have indicated that LMWHs possess efficacy and safety characteristics similar to intravenous heparin but are easier to administer. LMWH preparations vary considerably in their methods of preparation and pharmacological properties, and the relative efficacies of these various LMWHs remain to be determined by direct comparisons in randomized clinical trials.

Anticoagulants↗
PubMed1998

eagle is required for the specification of serotonin neurons and other neuroblast 7-3 progeny in the Drosophila CNS.

During development of the Drosophila nerve cord, neuroblast 7-3 gives rise to a pair of mitotic sister serotonin neurons in each hemisegment. Here we show that the zinc finger gene eagle, which is expressed in neuroblast 7-3, is essential for specifying the fate of serotonin neurons. We find that loss-of-function eagle mutations produce an unusual differential phenotype with respect to the sister serotonin cells and that eagle is necessary for the maintenance of engrailed and zfh-2 expression in the serotonin neurons. We present a model that uniquely identifies all progeny neurons in the neuroblast 7-3 lineage based on the expression of specific molecular markers, position within the nerve cord and the effect of eagle loss-of-function mutations. Although serotonin is an important neurotransmitter conserved throughout the animal kingdom, we show that hypomorphic alleles of eagle can produce viable adults that have a dramatic reduction in the number of serotonin-producing neurons.

5-Hydroxytryptophan↗