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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 199 records · Page 11Linked to original sources
PubMed1993

A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement.

BACKGROUND: Despite the use of warfarin, major systemic embolism remains an important complication in patients with heart-valve replacement. Although the addition of antiplatelet agents has the potential to reduce this complication, their efficacy and safety when given in combination with warfarin are uncertain. METHODS: In a randomized, double-blind, placebo-controlled trial, we assessed the efficacy and safety of adding aspirin (100 mg per day) to warfarin treatment (target international normalized ratio, 3.0 to 4.5) in 370 patients with mechanical heart valves or with tissue valves plus atrial fibrillation or a history of thromboembolism. RESULTS: A total of 186 patients were randomly assigned to aspirin and 184 to placebo, and they were followed for up to 4 years (average, 2.5). Major systemic embolism or death from vascular causes occurred in 6 aspirin-treated patients (1.9 percent per year) and 24 placebo-treated patients (8.5 percent per year) (risk reduction with aspirin, 77 percent; 95 percent confidence interval, 44 to 91 percent; P < 0.001). Major systemic embolism, nonfatal intracranial hemorrhage, or death from hemorrhage or vascular causes occurred in 12 patients assigned to aspirin (3.9 percent per year) and 28 patients assigned to placebo (9.9 percent per year) (risk reduction, 61 per cent; 95 percent confidence interval, 24 to 80 percent; P = 0.005); major systemic embolism or death from any cause occurred in 13 patients (4.2 percent) and 33 patients (11.7 percent), respectively (risk reduction, 65 percent; 95 percent confidence interval, 33 to 82 percent; P < 0.001); and death from all causes occurred in 9 patients (2.8 percent) and 22 patients (7.4 percent), respectively (risk reduction, 63 percent; 95 percent confidence interval, 19 to 83 percent; P = 0.01). Bleeding occurred in 71 patients in the aspirin group (35.0 percent), as compared with 49 patients in the placebo group (22.0 percent) (increase in risk, 55 percent; 95 percent confidence interval, 8 to 124 percent; P = 0.02); major bleeding occurred in 24 and 19 patients, respectively (increase in risk, 27 percent; 95 percent confidence interval, -30 to 132 percent; P = 0.43). CONCLUSIONS: In patients with mechanical heart valves and high-risk patients with prosthetic tissue valves, the addition of aspirin to warfarin therapy reduced mortality, particularly mortality from vascular causes, together with major systemic embolism. Although there was some increase in bleeding, the risk of the combined treatment was more than offset by the considerable benefit.

Adult↗
PubMed1993

Establishing a therapeutic range for heparin therapy.

OBJECTIVE: To compare two methods of determining a therapeutic range of activated partial thromboplastin time (aPTT) results. DESIGN: Cohort studies. SETTING: Referral teaching hospital. PATIENTS: Inpatients who received unfractionated heparin intravenously for venous thromboembolic disease. MEASUREMENTS: A therapeutic range determined by aPTT ratios of 1.5 to 2.5 times the control value as compared with a therapeutic range determined by protamine titration heparin levels of 0.2 to 0.4 U/mL. RESULTS: For all aPTT reagents studied, a ratio of 1.5 times the control value is much less than a minimum protamine titration heparin level of 0.2 U/mL. Various manufacturers' aPTT reagents and reagent lots from the same manufacturer show considerable variation in response to heparin and therefore have different therapeutic ranges. CONCLUSIONS: A different dose of heparin would be required to produce an aPTT ratio of 1.5 times the control value, depending on the reagent used. Establishing a therapeutic range for aPTT results using protamine titration heparin levels of 0.2 to 0.4 U/mL as a reference standard is practical and compensates for the variable response of aPTT reagents to heparin.

Cohort Studies↗
PubMed1993

Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy.

BACKGROUND: The anticoagulant activity of warfarin sodium is monitored by the prothrombin time (PT). The introduction of a portable PT monitor has raised the possibility that patients could reduce the inconvenience of anticoagulant therapy by measuring their PT at home. We performed this study to determine the feasibility and accuracy of home use of the portable PT monitor. METHODS: A prospective cohort study was performed in consecutive eligible patients who required long-term anticoagulant therapy. Patients performed multiple measurements of their PT at home by means of the portable monitor and at their usual laboratory within a 4-hour interval. The accuracy of the portable monitor was evaluated by two criteria for agreement. Standard agreement was achieved if the portable monitor and laboratory results were both either within or outside the patient's targeted therapeutic range or if the two results were within 0.4 international normalized ratio units of each other. Expanded agreement was achieved if both the portable monitor and laboratory results were within +/- 0.4 international normalized ratio units of the targeted therapeutic range. RESULTS: Forty patients (19 men and 21 women, aged 25 to 74 years) were followed up for 6 to 24 months by means of the portable PT monitor. The mean level of agreement achieved per patient was 83% (95% confidence interval, 79% to 87%) by the standard criteria and 96% (95% confidence interval, 94% to 98%) by the expanded criteria. Twenty-seven patients (68%) and 39 patients (98%) achieved more than 80% agreement by the standard and the expanded criteria, respectively. Questionnaire results revealed that 97% of the patients preferred using the portable monitor to measure their PT. CONCLUSIONS: Patients receiving long-term anticoagulant therapy achieved a high rate of clinically important agreement between self-measurements of the PT with the use of a portable monitor and laboratory PT results. Patients strongly preferred using the portable monitor to measure their PT levels. The use of the portable monitor as the primary method for measuring the PT can be recommended in selected patients receiving long-term anticoagulant treatment.

Administration, Oral↗
PubMed1993

The use of an indwelling Teflon catheter for subcutaneous heparin administration during pregnancy. A randomized crossover study.

BACKGROUND: The use of subcutaneous heparin, the therapy of choice for women requiring anticoagulant prophylaxis during pregnancy, is problematic because of the discomfort produced by repeated injections. An indwelling subcutaneous Teflon catheter that can be left in place for 1 week recently became available for use as an entry port for parenteral therapy. Since the use of this catheter has the potential to overcome some of the problems of long-term heparin therapy, we decided to compare this Teflon catheter with twice-daily subcutaneous injections in women requiring heparin during pregnancy. METHODS: In a randomized, multiple-crossover study, patients alternated every 2 weeks between having heparin administered through the indwelling Teflon catheter and receiving heparin via subcutaneous injections. After each 4-week cycle, patients completed a questionnaire designed to determine their preferred method of heparin administration. The side effects, doses, and anticoagulant activity of heparin with the two delivery systems were also compared. RESULTS: Twelve patients completed one to five 4-week cycles of heparin therapy. Ten of the patients selected the Teflon catheter as the preferred route of heparin administration (P = .04) and 11 patients reported that the catheter caused less pain and bruising than twice-daily subcutaneous injections (P < .01). Five patients developed urticarial reactions at the sites of heparin injections. These reactions tended to be more severe when the Teflon catheter was used, and two women discontinued using the catheter after the first cycle because of this complication. There were no differences in heparin dose requirements or achieved activated partial thromboplastin times between the two routes of heparin administration. CONCLUSIONS: Most pregnant women in our study preferred to have subcutaneous heparin administered through an indwelling Teflon catheter rather than by twice-daily injections. Heparin given through the Teflon catheter was bioavailable and caused less local bruising than twice-daily injections. Urticarial reactions to heparin tended to be more severe with the use of the Teflon catheter and resulted in the discontinuation of the device's use in two of 12 patients.

Adult↗
PubMed1993

An antithrombin III assay based on factor Xa inhibition provides a more reliable test to identify congenital antithrombin III deficiency than an assay based on thrombin inhibition.

OBJECTIVES: To determine whether functional antithrombin III (AT-III) levels measured by a factor Xa inhibition (AT-III-Xa) assay identifies AT-III deficient individuals more reliably than functional AT-III levels measured by a thrombin inhibition (AT-III-IIa) assay. STUDY DESIGN: Cross-sectional study. PATIENT POPULATION: Sixty-seven members of a large family with type 2 AT-III deficiency. INTERVENTION: DNA analysis was used as the reference diagnostic standard for AT-III status and subjects were classified as AT-III deficient or non deficient according to these results. Functional AT-III levels were measured in all subjects using: 1) a chromogenic substrate for thrombin and added human thrombin (AT-III-IIa), and 2) a chromogenic substrate for factor Xa and added bovine factor Xa (AT-III-Xa). Functional heparin cofactor II (HC-II) levels were measured using a commercially available kit. The proportions of 125I-alpha-thrombin complexed to AT-III and HC-II were measured by polyacrylamide gel electrophoresis and autoradiography. RESULTS: Thirty-one (46%) individuals were classified as AT-III deficient and 36 (54%) as AT-III non deficient. AT-III-Xa assay measured a significantly lower mean AT-III value and a narrower range for individuals classified as AT-III deficient than the AT-III-IIa assay. Using the AT-III-IIa assay, six subjects had borderline AT-III levels compared to none with the AT-III-Xa assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

125I-fibrinogen leg scanning: reassessment of its role for the diagnosis of venous thrombosis in post-operative patients.

OBJECTIVE: To determine the reasons why 125I-fibrinogen leg scanning, a screening test which was reported to be very sensitive for the detection of post-operative thrombosis, has shown poor sensitivity in contemporary studies. STUDY IDENTIFICATION: English-language reports were identified through a Medline computer search (1965-1991), Current Contents, and an extensive manual search of the bibliographies in identified articles. STUDY SELECTION: Studies in orthopaedic or general surgical patients were reviewed that compared 125I-fibrinogen leg scanning with venography in all patients (accuracy studies) or in patients in whom 125I-fibrinogen leg scanning became positive (positive predictive value studies). DATA EXTRACTION: A systematic appraisal of study design and specific descriptive information concerning the selection of patients. RESULTS OF DATA SYNTHESIS: Six of the 15 studies which compared 125I-fibrinogen leg scanning with venography were level 1 studies (potential for bias minimized) and nine were classified as level 2 studies (potential for bias not minimized). In orthopaedic surgical patients, the pooled sensitivity of leg scanning for isolated calf vein thrombosis, for all venous thrombosis, and the pooled specificity were 55%, 45%, and 92% for the level 1 studies, respectively. These indices were 88%, 82%, and 79%, respectively for the level 2 studies (P < 0.001). Only two (level 2) studies were found that evaluated the accuracy of leg scanning for venous thrombosis in general surgical patients. CONCLUSION: We conclude that leg scanning is an insensitive method for the screening of post-operative venous thrombosis in orthopaedic patients. Our findings call into question the validity of the many studies (including meta-analyses) evaluating prophylactic agents for venous thrombosis which used leg scanning as the only test for the assessment of efficacy.

Fibrinogen↗
PubMed1993

Limitations of impedance plethysmography in the diagnosis of clinically suspected deep-vein thrombosis.

OBJECTIVE: To re-evaluate the accuracy of impedance plethysmography (IPG) for the detection of proximal deep-vein thrombosis (DVT). PATIENTS: A total of 384 of 390 consecutive outpatients referred with their first episode of clinically suspected deep-vein thrombosis. SETTING: University-based tertiary care medical center associated with a cancer clinic. DESIGN: A retrospective analysis of a cohort of patients whose data were recorded and stored prospectively on a computerized data base over a 22-month period. MEASUREMENTS: Patients were evaluated by a physician and underwent IPG testing. Patients with abnormal IPG tests and those with normal IPG results in whom there was a high clinical suspicion of DVT or in whom follow-up IPG testing was not feasible were referred for venography. Venography and IPG results were interpreted by a panel of independent observers. Two models of the IPG instrument were used (Codman 200 and Electrodiagnostic Instruments 800). RESULTS: Venography (or compression ultrasound) was done in 57 patients with an abnormal IPG test and in 85 patients with normal IPG results. Impedance plethysmography was abnormal in only 37 of 56 patients with confirmed proximal-vein thrombosis (sensitivity, 66%; 95% Cl, 52% to 78%). Of the 57 patients with an abnormal IPG result, 37 had DVT (positive predictive value, 65%). The sensitivity for the detection of proximal DVT did not differ between the IPG 200 and 800 instruments (sensitivity, 63% and 71%, respectively; P > 0.2). Of the 19 proximal-vein thrombi not detected by IPG, 12 (63%) were occlusive and 11 (58%) involved at least the popliteal and superficial femoral veins. CONCLUSIONS: At our center, IPG has a far lower sensitivity for proximal-vein thrombosis than has been previously reported for symptomatic outpatients. The reason for this low sensitivity is unclear. Our findings indicate that centers using IPG as the initial diagnostic test for suspected DVT should be aware of this potential problem and should consider re-evaluating the sensitivity of their IPG machines by performing venography in a cohort of their patients with normal test results.

Female↗
PubMed1993

Type 1 plasminogen activator inhibitor is not an acute phase reactant in rats. Lack of IL-6- and hepatocyte-dependent synthesis.

The contributing role of hepatocytes and IL-6 in the acute phase-like elevation of plasma type 1 plasminogen activator inhibitor (PAI-1) in vivo is not known. We addressed this question by comparing the effects of two inflammatory stimuli known to increase plasma concentrations of IL-6 on the plasma concentrations and site of synthesis of PAI-1 and cysteine proteinase inhibitor (CPI) in rats. Subcutaneous injection of turpentine results in a sustained increase in plasma IL-6 and CPI Ag levels over a 24-h period. In contrast, plasma PAI-1 activity was not altered by turpentine treatment. Northern blot analysis of poly(A)+ mRNA extracted from freshly isolated hepatocytes of saline- or turpentine-treated animals demonstrated induction of CPI mRNA expression but failed to detect basal or induced PAI-1 or IL-6 mRNA expression. However, PAI-1 mRNA was detected in rat hepatocytes in primary culture for 24 h and was induced by dexamethasone. Intravenous infusion of bacterial LPS (4 mg/kg) induced a sustained increase in plasma CPI Ag and transient increases in plasma IL-6 and PAI-1. Northern blot analysis of freshly isolated, fractionated liver cells indicated that LPS treatment (3 h) induced PAI-1 mRNA expression most significantly in the endothelial and Kupffer cell fractions. IL-6 mRNA expression was induced in Kupffer cells and CPI mRNA was induced in hepatocytes. Immunocytochemical analysis revealed LPS-induced accumulation of PAI-1 Ag associated with the vascular endothelium, subendothelial matrix, and sinusoidal lining cells. Our results indicate that PAI-1 mRNA is not significantly expressed by rat hepatocytes in vivo and that plasma PAI-1 levels are not influenced by increased IL-6 expression in Kupffer cells or in plasma.

Acute-Phase Proteins↗
PubMed1993

Tissue-specific alternative splicing of the Drosophila dopa decarboxylase gene is affected by heat shock.

The Drosophila dopa decarboxylase gene, Ddc, is expressed in the hypoderm and in a small number of cells in the central nervous system (CNS). The unique Ddc primary transcript is alternatively spliced in these two tissues. We investigated whether Ddc splicing in the CNS is a general property of the CNS or a unique property of the cells that normally express Ddc by expressing the Ddc primary transcript ubiquitously under the control of an Hsp70 heat shock promoter. Under basal expression conditions, Ddc splicing shows normal tissue specificity, indicating that the regulation of Ddc splicing in the CNS is tissue specific rather than cell specific. Previous studies have shown that severe heat shock blocks mRNA splicing in cultured Drosophila melanogaster cells. Our results show that splicing of the heat shock-inducible Hsp83 transcript is very resistant to heat shock. In contrast, under either mild or severe heat shock, the splicing specificity of the heat shock-induced Ddc primary transcript is affected, leading to the accumulation of inappropriately high levels of the CNS splice form in non-CNS tissues. The chromosomal Ddc transcript is similarly affected. These results show unexpected heterogeneity in the splicing of individual mRNAs as a response to heat shock and suggest that the Ddc CNS-specific splicing pathway is the default.

Alternative Splicing↗
PubMed1993

Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis.

Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when alpha 2-antiplasmin levels fall, and this may contribute to t-PA-induced hemorrhage. Because clot-bound plasmin is protected from alpha 2-antiplasmin inhibition, we tested the possibility that alpha 2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleeding without affecting thrombolysis. When added to human or rabbit plasma, alpha 2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but hat little effect on the lysis of 125I-fibrin clots. To examine its effect in vivo, rabbits with preformed 125I-labeled-jugular vein thrombi were randomized to receive t-PA, t-PA and alpha 2-antiplasmin, or saline. alpha 2-Antiplasmin infusion produced a modest decrease in t-PA-induced thrombolysis (from 40.2% to 30.1%, P = 0.12), but reduced fibrinogen consumption from 87% to 27% (P = 0.0001), and decreased blood loss from standardized ear incisions from 5,594 to 656 microliter (P < 0.0001). We hypothesize that alpha 2-antiplasmin limits t-PA-induced hemorrhage by inhibiting fibrinogenolysis and subsequent fragment X formation because (a) SDS-PAGE and immunoblot analysis indicate less fragment X formation in alpha 2-antiplasmin treated animals, and (b) when added to a solution of fibrinogen and plasminogen clotted with thrombin in the presence of t-PA, fragment X shortens the lysis time in a concentration-dependent fashion. These findings suggest that fragment X incorporation into hemostatic plugs contributes to t-PA-induced bleeding. By blocking t-PA-mediated fibrinogenolysis, alpha 2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators.

Animals↗
PubMed1993

Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass.

BACKGROUND: Heparin rebound, the reappearance of anticoagulant activity after adequate neutralization with protamine, can lead to excessive postoperative bleeding after cardiac surgery. We investigated the mechanism of heparin rebound by using chemically modified heparin that lacks anticoagulant activity (low-affinity heparin) but that is able to displace protein-bound anticoagulantly active heparin. METHODS AND RESULTS: Sixteen patients undergoing elective cardiac surgery were given heparin (400 U/kg) to achieve an activated clotting time (ACT) > 400 seconds. After cardiopulmonary bypass, protamine sulfate was given (by heparin-ACT dose-response curve) to return the ACT to prebypass times (preoperative, 160 +/- 9 seconds; postoperative, 156 +/- 17 seconds). Blood samples were obtained serially for 24 hours and assayed for thrombin clotting time (TCT) and heparin activity using an anti-factor Xa assay. The TCT and anti-factor Xa activity were consistently and abnormally elevated for the first 6 hours after surgery. The anti-factor Xa activity increased fourfold after the addition of low-affinity heparin (essentially free of anti-factor Xa activity), indicating that anticoagulantly active heparin persisted in the circulation after protamine neutralization bound nonspecifically to plasma proteins. Blood loss correlated with postoperative TCTs. CONCLUSIONS: Our findings demonstrate that heparin anticoagulant activity persists for up to 6 hours after surgery despite apparent protamine neutralization. The observation of the marked increase in plasma anti-factor Xa activity after the addition of low-affinity heparin suggests that after its administration, a large proportion of the heparin binds to plasma proteins and is incompletely removed by protamine. After protamine is cleared, the protein-bound heparin dissociates slowly and binds to anti-thrombin III to produce an anticoagulant effect.

Antithrombin III↗
PubMed1993

New anticoagulant strategies.

The limitations of standard heparin have prompted the development of a variety of newer antithrombotic agents. In fact, a LMWH preparation has recently been approved for clinical use in North America. Of these novel preparations, LMWH, the direct thrombin inhibitors, and inhibitors of GPIIb-IIIa have been used clinically and are in advanced stages of evaluation. Not only is LMWH effective in the prevention of venous thromboembolic disease in high-risk patients, but its more predictable dose response makes it an ideal candidate for the treatment of venous thrombosis. Further studies are needed to determine whether LMWH is superior to standard heparin as adjunctive therapy in patients undergoing coronary thrombolysis or angioplasty. Particularly promising in the setting of arterial thrombosis are hirudin, hirulog, and 7E3. With the encouraging results reported to date, it is likely that these agents will soon find their way into the treatment armamentarium of arterial thrombosis.

Amino Acid Sequence↗
PubMed1992

Evidence that postoperative fibrinolytic shutdown is mediated by plasma factors that stimulate endothelial cell type I plasminogen activator inhibitor biosynthesis.

Postoperative fibrinolytic shutdown has been attributed to an increase in plasma levels of type I plasminogen activator inhibitor (PAI-1) activity and may contribute to postoperative venous thrombosis. The purpose of this study was to determine whether the postoperative increase in PAI-1 is contributed to by a plasma mediator(s) that stimulates PAI-1 synthesis and secretion by vascular endothelium. Plasma samples collected from patients (N = 11) before and after surgery for total hip replacement were (1) assayed for endogenous plasma PAI-1 antigen and activity, and (2) incubated with cultured human umbilical vein endothelial cells (HUVECs) and PAI-1 antigen and activity measured in the conditioned medium (CM). Eighteen hours after surgery, endogenous plasma levels of PAI-1 antigen and activity were increased by 225% (P = .003) and 190% (P = .04), respectively over the preoperative values. In addition, compared with preoperative plasma, postoperative plasma increased HUVEC secretion of PAI-1 antigen and activity by 99% (P = .001) and 66% (P = .002), respectively. This increase in HUVEC PAI-1 secretion reflects an increase in PAI-1 mRNA expression and protein biosynthesis as confirmed by metabolic radiolabeling, immunoprecipitation, and Northern blot analysis. Ultra-filtration experiments indicate that the postoperative plasma mediator(s) that stimulates HUVEC PAI-1 biosynthesis is in a molecular weight (MW) range of approximately 30 to 100 Kd. Heat treatment (56 degrees C; 30 minutes) of postoperative plasma abolished the induction of HUVEC PAI-1 production. Enzyme-linked immunosorbent assay and immunoneutralization experiments indicate that tumor necrosis factor-alpha (TNF alpha) and interleukin-1 alpha (IL-1 alpha) do not contribute to the postoperative plasma effect on HUVEC PAI-1 synthesis. These observations demonstrate that postoperative patient plasma contains a factor(s) that may stimulate endothelial cell PAI-1 biosynthesis in vivo and thus mediate postoperative fibrinolytic shut-down.

Aged↗
PubMed1992

Heparin enhances active site-dependent binding of tissue-type plasminogen activator to endothelial cells.

Human umbilical vein endothelial cells (HUVEC) in culture express two classes of binding sites for tissue-type plasminogen activator (t-PA). The high-affinity binding site has been identified as PA inhibitor type 1 (PAI-1), which binds to the catalytic portion of the molecule, while the second site binds t-PA through an active-site independent domain. Because recombinant t-PA (rt-PA) is often administered concomitantly with heparin, we investigated the effects of heparin on rt-PA binding to HUVEC. Preincubation of HUVEC with heparin at 4 degrees C increased the binding of radiolabeled rt-PA in a time- and dose-dependent manner. One-half maximal increase in binding was observed within 10 minutes of heparin addition. When HUVEC were preincubated with optimal concentrations (5 U/mL) of heparin for 4 hours at 4 degrees C, a 2.5- +/- 0.2-fold increase in specific binding was observed (mean +/- SEM, n = 12, P less than .01). Other highly sulfated glycosaminoglycans and fucoidan (a sulfated polymer of fucose) stimulated rt-PA binding as well, whereas glycosaminoglycans with lower sulfate content than heparin did not. Several results suggested that heparin increased the binding of rt-PA to "cell-associated" PAI-1. First, only active-site-dependent binding was enhanced by heparin, whereas binding of active-site blocked rt-PA was not affected. Second, extracts from HUVEC preincubated with heparin contained increased amounts of rt-PA-PAI-1 complexes as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Third, antibodies to PAI-1 blocked the increased binding entirely. HUVEC preincubated with heparin also bound increased amounts of enzymatically active radiolabeled urokinase-type PAs. However, HUVEC preincubated with heparin did not express increased amounts of immunoreactive PAI-1. Therefore, heparin, at therapeutic concentrations, may enhance or stabilize the association of PAs with endothelial cell-associated PAI-1.

Binding Sites↗
PubMed1992

Ventilation-perfusion lung scanning and the diagnosis of pulmonary embolism: improvement of observer agreement by the use of a lung segment reference chart.

OBJECTIVE: To test the hypothesis that the systematic use of a lung segment reference chart can improve the inter- and intra-observer agreement for the interpretation of ventilation-perfusion lung scans. DESIGN: A randomized trial. STUDY POPULATION: Ventilation-perfusion lung scans were obtained in a series of 220 consecutive patients with clinically suspected pulmonary embolism. INTERVENTION: Ventilation-perfusion scans were randomly allocated to one of two series each consisting of 110 ventilation-perfusion lung scans. The first series of lung scans was interpreted according to the routine diagnostic approach, and the second series was interpreted with the mandatory use of a lung segment reference chart on which observed ventilation and perfusion defects were drawn. The two nuclear medicine physicians agreed a priori on the diagnostic criteria of the classification scheme. MEASUREMENTS: Lung scans were classified as normal, non-high probability, or high probability for pulmonary embolism. The extent of disagreement between the nuclear medicine physicians (inter-observer disagreement) and the lack of internal consistency of each nuclear medicine physician (intra-observer disagreement) was assessed by the percentage disagreement and by kappa statistic. RESULTS: Inter-observer disagreement which was 20% in the first series, decreased significantly in the second series to 7%; P = 0.003. Intra-observer disagreement for the first series was 10% and 22% for the nuclear medicine physicians, respectively. Intra-observer disagreement for the second series of lung scans decreased significantly for one nuclear medicine physician (intra-observer disagreement, 0%; P less than 0.01), whereas intra-observer disagreement was reduced to 10% for the other nuclear medicine physician (P = 0.09). CONCLUSION: Inter- and intra-observer disagreement were significantly reduced when two nuclear medicine specialists interpreted ventilation-perfusion lung scans according to the routine diagnostic approach plus the use of a lung segment reference chart. The use of the lung segment reference chart for the interpretation of lung scans is likely to improve the management of patients with clinically suspected pulmonary embolism.

Humans↗
PubMed1992

Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin.

Thrombus extension in patients with venous thromboembolism is due to the accretion of fibrin onto existing thrombi. Extension is promoted by both circulating and thrombus-bound thrombin, which convert fibrinogen to fibrin. Heparin is an effective antithrombotic agent, but it requires continuous administration to achieve persistent inhibition of thrombus extension. Heparin is highly effective in inhibiting fluid phase thrombin, but is a relatively ineffective inhibitor of thrombus-bound thrombin. Hirudin, unlike heparin, inactivates both circulating and fibrin-bound thrombin and, therefore, has the potential to prevent thrombus extension even after a short course of treatment. The aim of this study was to evaluate the time course of the accretion of new fibrin onto preexisting rabbit jugular vein thrombi after a 3-hour infusion of saline, heparin, and hirudin. Heparin and recombinant (r)-hirudin (CGP 39399) were infused at doses that doubled the activated partial thromboplastin time (aPTT). At the end of the 3-hour infusions in rabbits treated with saline, heparin (0.75 mg/kg), or r-hirudin (1.25 mg/kg), accretion of 125I-fibrinogen was 59 +/- 5 micrograms, 34 +/- 4 micrograms, and 21 +/- 2 micrograms, respectively (heparin and r-hirudin v saline, P less than .01; r-hirudin v heparin, P less than .01). Three hours after the end of the infusions, the accreted 125I-fibrinogen in the saline-, heparin-, and hirudin-treated animals was 89 +/- 6 micrograms, 51 +/- 7 micrograms, and 23 +/- 3 micrograms, respectively; 9 hours after the end of the infusions, the accreted 125I-fibrinogen was 112 +/- 9 micrograms, 82 +/- 7 micrograms, and 25 +/- 3 micrograms, respectively. aPTT and thrombin clotting time (TCT) returned to the baseline value 90 minutes after the end of heparin or r-hirudin infusion. During in vitro experiments, human fibrin clots previously incubated in human plasma containing r-hirudin did not promote fibrinopeptide A (FPA) generation when washed and then incubated in human plasma in the absence of thrombin inhibitors. This persistent inhibition of FPA production was not observed after incubation in human plasma of human plasma clots preincubated with heparin. We conclude that heparin is effective in inhibiting thrombus extension while it is present in the circulation, but that this effect is rapidly lost after its plasma clearance. In contrast, the antithrombotic activity of r-hirudin is sustained beyond its plasma clearance, presumably because of its ability to inactivate thrombus-bound thrombin. Our findings indicate that r-hirudin might be an effective antithrombotic agent even when used for short periods.

Animals↗