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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 19 recordsLinked to original sources
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↗
PubMed1992

The effect of thrombin inhibitors on tissue plasminogen activator induced thrombolysis in a rat model.

Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Chloromethyl Ketones↗
PubMed1992

Heparin binding to plasma proteins, an important mechanism for heparin resistance.

Heparin dosage requirements vary widely among patients with venous thromboembolism. In this study, we measured the proportion of anticoagulantly-active heparin which was reversibly bound and neutralized by plasma proteins (defined as reversible heparin neutralization) in the pre-treatment plasma (in vitro) and in the 6 h post-treatment plasma (ex vivo) of patients with venous thromboembolism treated with a fixed dose of heparin. Reversible heparin neutralization was assessed by comparing the heparin levels measured as anti-factor Xa activity before and after the addition of low affinity heparin which is essentially devoid of anti-factor Xa activity, in order to displace heparin bound to plasma proteins. The results indicate that reversible heparin neutralization due to binding to plasma proteins is a major determinant of the anticoagulant response to a fixed dose of standard heparin 6 h post-treatment and of the eventual heparin dose required to achieve a therapeutic anticoagulant effect on days 3-5 of heparin treatment.

Adult↗
PubMed1992

Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of alpha-thrombin.

Hirudin and hirulog-1 [D-Phe-Pro-Arg-Pro-[Gly]4-desulphohirudin-(54-65)] abrogate the enzyme activities of alpha-thrombin by binding the enzyme simultaneously at its catalytic centre and fibrin(ogen)-recognition exosite. In contrast, hirugen [hirudin-(54-65)] binds alpha-thrombin solely at the fibrin(ogen)-recognition exosite, and competitively inhibits fibrinopeptide A release. To investigate the extent to which the fibrin(ogen)-recognition exosite is involved when alpha-thrombin catalyses the amplification reactions of coagulation, we compared the abilities of hirudin, hirulog-1 and hirugen to inhibit simultaneously Factor X, Factor V and prothrombin activation. Whereas 0.1 microM-hirudin and 0.1 microM-hirulog-1 (i.e. less than 10% of the concentration of prothrombin in plasma) inhibited Factor X, Factor V and prothrombin activation, 10 microM was the minimum concentration of hirugen to achieve a similar anticoagulant action. Concentrations of hirudin and hirulog-1 equimolar to and 5 times greater than those of alpha-thrombin respectively abrogated Factor V activation by exogenous alpha-thrombin. In contrast, a 500-fold molar excess of hirugen could not. The inability of hirugen to inhibit the activation of the three clotting factors effectively suggests that the fibrin(ogen)-recognition exosite does not play a mandatory role when thrombin activates Factor V.

Amino Acid Sequence↗
PubMed1992

Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review.

PURPOSE: To estimate the prevalence of objectively proven thrombotic complications in antithrombin-III-deficient persons. STUDY DESIGN: Cross-sectional study and a critical review of the literature. DATA SOURCES AND EXTRACTION: The prevalence of thrombosis in antithrombin III-deficient and -nondeficient family members of a large kindred was estimated by history, review of diagnostic tests, and examination for venous reflux by Doppler ultrasonography, as an indicator of previous venous thrombosis. A MEDLINE search and literature review of the published English- and French-language literature from 1966 to 1990 that described antithrombin-III-deficient families was done, and the following information was obtained: the prevalence of thrombosis in deficient and nondeficient family members, the presence or absence of risk factors for thrombosis (surgery, pregnancy, the postpartum state, use of oral contraceptives, immobilization, metastatic cancer, major trauma) at the time of the thrombotic event, and age of onset of the first episode of thrombosis. The validity of the studies was assessed according to predetermined criteria. RESULTS: Sixty-seven research subjects were evaluated. Six of 31 (19.4%) antithrombin-III-deficient subjects compared with none of 36 (0%) nondeficient subjects had had one or more thrombotic events. The initial episode in five of six subjects had occurred in association with risk factors for thrombosis. The literature search indicated that the pooled prevalence of symptomatic venous thrombosis among the deficient subjects was 51%, but objective testing was done in only 17% of these subjects at the time of presentation. CONCLUSION: Based on the data from this antithrombin-III-deficient kindred, lifelong anticoagulant prophylaxis does not appear to be warranted in asymptomatic carriers, and prophylaxis could be limited to periods of high risk for thrombosis.

Adolescent↗
PubMed1992

Prevention of venous thromboembolism after surgery: a review of enoxaparin.

This review discusses the problem of deep vein thrombosis (DVT) after operation and identifies three levels of risk of DVT: low (less than 10 per cent), moderate (10-40 per cent) and high (40-80 per cent). Special emphasis is placed on the most recent prophylactic treatment, low molecular weight heparins (LMWHs), particularly enoxaparin. Several LMWHs are now available, but they differ slightly and each must be evaluated on its own merits. In general, however, LMWHs are both effective and safe in those patients at moderate or high risk of DVT. Thromboprophylaxis is cost effective when analysed using health-economic methodology.

Adult↗
PubMed1992

Antithrombotic therapy in deep vein thrombosis and pulmonary embolism.

After 50 years of clinical use anticoagulants are still the mainstay of treatment for venous thromboembolism. Several studies have demonstrated that failure to attain or to maintain an adequate anticoagulant effect with heparin after venous thromboembolism is associated with an increased risk of recurrence. The safety and effectiveness of heparin administered by continuous intravenous infusion has been compared with administration by intermittent intravenous injection; three studies reported less bleeding with the former. The relative efficacy and safety of continuous intravenous and intermittent subcutaneous heparin appear to be comparable. The readily available and relatively inexpensive activated partial thromboplastin time test is used most commonly to monitor heparin therapy. Recent audits indicate that current practices in the administration of heparin are often suboptimal because of an inadequate starting dose, a delay in obtaining or responding to activated partial thromboplastin time test results, or inappropriate adjustments of heparin doses. Attempts have recently been made to improve practices in the administration of heparin by developing a standardization protocol. Recommendations for patient management are discussed.

Blood Coagulation↗
PubMed1992

The zfh-2 gene product is a potential regulator of neuron-specific dopa decarboxylase gene expression in Drosophila.

We have studied a 40-bp upstream regulatory region of the DOPA decarboxylase gene (Ddc) which is important for cell-specific expression in the Drosophila central nervous system (CNS). This region contains two redundant elements which when simultaneously mutated result in lowered DDC expression in serotonin neurons. We uncovered a protein binding site within one of these elements and have cloned a factor which binds to the site. This factor is the product of the zfh-2 gene, a complex homeodomain/zinc finger protein previously identified by binding to an opsin regulatory element. The in vivo profile of ZFH-2 in the larval CNS shows intriguing overlap with DDC in specific serotonin and dopamine neurons. We show that ZFH-2 is related to a human transcription factor ATBF1. The multiple homeodomain and zinc finger motifs in these two proteins show a similar linear arrangement which implies coordinate action among the motifs. In addition, the homology defines a new homeodomain subtype.

Amino Acid Sequence↗
PubMed1992

The effect of high-dose nifedipine on renal hemodynamics of cyclosporine-treated renal allograft recipients.

Cyclosporine has been shown to reduce renal perfusion and to decrease glomerular filtration rate. Experimental studies suggest that nifedipine might reverse this renal vasoconstrictive effect of cyclosporine. We studied renal hemodynamics of 5 cyclosporine-treated renal transplant recipients before and after 2 weeks of therapy with high-dose nifedipine (up to 120 mg/day). Pretreatment GFR and renal plasma flow (RPF) were decreased. Following administration of nifedipine, RPF increased by 18% (P less than 0.01), while GFR did not change. Filtration fraction decreased by 10.5% (P less than 0.01). Mean arterial pressure declined from 111 +/- 5 to 96 +/- 3 mmHg (P less than 0.01). Renal vascular resistance dropped by 25% (P less than 0.01). Calculated postglomerular plasma flow increased by 20.5% (P less than 0.01). Urinary albumin excretion rate was unaffected. Cyclosporine whole blood levels were unchanged. The increase in RPF and in postglomerular plasma flow suggests that high-dose nifedipine might lessen cyclosporine-induced glomerular and interstitial ischemia in renal allograft recipients.

Adult↗
PubMed1992

Antithrombins: their potential as antithrombotic agents.

The inhibition of thrombin is the key to the prevention and treatment of thrombotic disorders. Although heparin is an extremely effective anticoagulant, it has certain limitations that are not shared by newer thrombin inhibitors. As a result, these novel inhibitors may have advantages over heparin in certain clinical settings.

Antithrombins↗