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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 271 records · Page 15Linked to original sources
PubMed1990

A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism.

Experiments in animals have demonstrated that recombinant tissue plasminogen activator (rt-PA) produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is both increased and accelerated, and bleeding is reduced when rt-PA is administered over a short period. In previous studies in patients with thrombotic disease, rt-PA has been shown to be an effective thrombolytic agent when administered by continuous infusion over a period between 90 minutes and 8 hours. To determine whether a short course regimen of rt-PA can achieve thrombolysis, a double-blind randomized trial has been conducted in which patients with objectively established acute symptomatic pulmonary embolism who were receiving heparin were allocated to either a 2-minute infusion of rt-PA at a dose of 0.6 mg/kg (33 patients) or saline placebo (25 patients). Perfusion lung scanning was used to assess the change in pulmonary perfusion at 24 hours and seven days post-study drug administration. Thirty-four percent of the rt-PA patients had a greater than 50 percent resolution in the perfusion defect at 24 hours compared to 12 percent of placebo patients (p = 0.026). At 24 hours, the mean relative improvement in the perfusion defect was 37.0 percent in rt-PA treated patients compared to 18.8 percent in the placebo group (p = 0.017). By day 7, no difference in lung scan resolution was detected between the groups. There were no major bleeds in either group nor were there any differences in transfusion requirements between groups. Minor bleeding occurred in 15 of the rt-PA patients mainly at angiogram-catheter insertion and venipuncture sites. These results suggest that a bolus regimen of rt-PA produces accelerated thrombolysis and provides an alternative and convenient approach to thrombolytic therapy in patients with pulmonary embolism.

Acute Disease↗
PubMed1990

From unfractionated heparins to low molecular weight heparins.

Interest in low molecular weight heparins as potential antithrombotic agents has been stimulated by two observations. These were that low molecular weight heparins have a different anticoagulant profile from unfractionated heparin and that some low molecular weight heparins are less haemorrhagic in animal models than unfractionated heparins for equivalent antithrombotic effects. Subsequently, it was shown that low molecular weight heparins inhibit platelet function and impair vascular permeability less than unfractionated heparin and that low molecular weight heparins have a longer biological half-life than unfractionated heparin. A number of low molecular weight heparins have been evaluated in clinical trials in general surgery, orthopaedic surgery and in the treatment of venous thrombosis. Low molecular weight heparins are highly effective in orthopaedic surgery where they appear to be more effective than unfractionated heparin. Low molecular weight heparins have also been shown to be either as effective or more effective than unfractionated heparin in preventing post-operative thrombosis following general surgery. In preliminary studies, low molecular weight heparins appear to be as effective as unfractionated heparin in the treatment of venous thrombosis but larger studies are required using clinically relevant outcome measures.

Animals↗
PubMed1990

Effect of verapamil on intestinal absorption of calcium in the rat.

The effect of verapamil in vitro, and the in vivo effect of both oral and parenteral verapamil administration on intestinal absorption was tested using everted gut sacs of duodenum, jejunum, distal ileum and proximal colon in rats. In the in vivo study, the effect of verapamil on blood levels of calcium, phosphorus and 1.25(OH)2D3, was investigated and a complete calcium balance was performed. In vitro, verapamil (1.5 mM) inhibited calcium absorption by the duodenum and colon only. Oral verapamil led to a reduction in the blood level of 1.25(OH)2D3. However, both oral and parenteral verapamil had no effect on the intestinal absorption, urinary secretion and consequently on the calcium balance.

Animals↗
PubMed1990

Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Results of a randomized trial.

We performed a randomized trial comparing two dosing regimens of recombinant tissue plasminogen activator (rt-PA) plus heparin vs heparin alone in the treatment of acute proximal deep vein thrombosis in 83 patients. Of 12 patients who received 0.5 mg/kg rt-PA plus heparin over 4 h, seven (58 percent) had greater than 50 percent lysis of the thrombus, compared with none of 12 who received placebo plus heparin (p = 0.002). Of 28 patients who received 0.5 mg/kg rt-PA over 8 h, repeated in 24 h, six (21 percent) had greater than 50 percent lysis, compared with two (7 percent) of 30 patients who received placebo plus heparin (p = 0.11). The 4-h infusion of rt-PA produced a 40 percent reduction and the 8-h infusion an 11 percent reduction in plasma fibrinogen concentration. At long-term follow-up, three (25 percent) of 12 patients in whom greater than 50 percent lysis was achieved had symptoms of the postphlebitic syndrome, compared with 19 (56 percent) of 34 patients in whom lysis was less than 50 percent (p = 0.07).

Double-Blind Method↗
PubMed1990

Comparison of platelet scintigraphy, impedance plethysmography gray scale and color flow duplex ultrasound and venography for the diagnosis of venous thrombosis.

The several techniques available for the diagnosis of venous thrombosis have not been directly compared in the same patient population. Thus color and gray scale duplex ultrasound (U), impedance plethysmography (IPG), 3-4 hr platelet imaging (PS) were compared to venography (V), in 104 consecutive patients (in hospital and out). PS and V were read by two, and IPG and U by one, blinded reader. Comparisons were made for the calf (CA), popliteal (Pop) and femoral (Fem) vessels. Reproducibility of V and PS was 84 and 87%. (table; see text) We conclude that PS, while having a very high specificity, has an unacceptably low sensitivity. However, while both impedance plethysmography and color flow ultrasound have excellent and similar diagnostic accuracy in the femoral, these techniques have either a low sensitivity or low technical success rate in the calf or popliteal veins.

Blood Platelets↗
PubMed1990

Prevention of venous thrombosis in patients undergoing major orthopaedic surgical procedures.

Patients having major orthopaedic surgical procedures have a high risk of venous thromboembolism. The distribution of thrombi following hip surgery differs from most other high risk situations, as 30-40% of all thrombi occur in proximal veins and many are unassociated with distal vein thrombosis. Many of these thrombi are undetected by currently available screening tests, but are detected by venography. Of the various prophylactic methods available, oral anticoagulants, adjusted-dose heparin and low molecular weight heparins are most effective in hip surgery, and oral anticoagulants and external pneumatic compression are most effective in knee surgery.

Bone and Bones↗
PubMed1989

The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement.

Studies in experimental animals have demonstrated that there is a relationship between levels of low molecular weight (LMW) heparin and both bleeding and inhibition of thrombosis. The relationship between these outcomes and ex vivo anti-factor Xa levels has been examined in 163 patients undergoing total hip replacement who were given prophylaxis once daily with a LMW heparin (enoxaparine). Fifty patients received 60 mg of enoxaparine and 113 received 40 mg, both regimens being administered subcutaneously once daily. Blood samples for anti-factor Xa levels were collected 12 hours after the injection on the day of surgery and on days 1, 3 and 6, postoperatively. The incidence of wound hematoma was 5.3% when the maximum anti-factor Xa level was less than or equal to 0.2 units per ml, but increased to 24.5% when the anti-factor Xa level exceeded 0.2 units per ml, P = 0.0008. The incidence of postoperative thrombosis was low (6.3%) if the minimum anti-factor Xa level exceeded 0.1 units per ml, but increased to 14.6% when less than or equal to 0.1 units per ml, and to 18.8% if the anti-factor Xa level was less than or equal to 0.05 units per ml. Regression analysis revealed that there was a statistically significant relationship between anti-factor Xa level and wound hematoma, P = 0.002 and anti-factor Xa level and thrombosis, P = 0.03. These findings suggest that when enoxaparine is administered as a once daily subcutaneous injection, the 12 hour anti-factor Xa level should not exceed 0.2 units per ml to minimize bleeding and levels greater than 0.05 units per ml should be obtained to optimize efficacy.

Factor Xa Inhibitors↗
PubMed1989

An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery.

Venous thromboembolism is a common post-operative complication in patients following hip surgery. 125I-fibrinogen leg scanning and impedance plethysmography (IPG), are often used in the detection of venous thrombi in such patients. Information on the sensitivity and specificity of these non-invasive tests for the diagnosis of venous thrombosis following hip surgery is relevant for both patient management and for choosing the appropriate outcome measure for clinical trials evaluating new prophylactic regimens. We determined the sensitivity and specificity of the IPG alone, the 125I-fibrinogen leg scan alone, as well as the combined use of the two tests from a retrospective analysis of 685 hip surgery patients who participated in clinical trials of anti-thrombotic prophylaxis. These patients were followed prospectively with non-invasive tests. Bilateral venography was attempted either when one or both screening tests became positive or on day 10-14 post-operatively if both screening tests remained negative. Adequate venography was obtained in 1,010 (73.7%) legs and thrombi were identified in 198 (19.6%) legs. The sensitivities of the IPG and leg scanning were 12.9% and 44.6% respectively; the corresponding specificities were 98.1% and 95.0%. The sensitivity of a positive result on one or both screening tests was 49.6% with a specificity of 93.9%. Therefore, leg scanning and IPG, even in combination, are not sufficiently accurate to be recommended as the only strategy for the diagnosis of venous thrombosis following hip surgery. Venography should be considered in all patients undergoing surveillance testing either when one or both of the screening tests become positive or on day 10-14 if the screening tests remain negative.

Fibrinogen↗
PubMed1989

Congenital antithrombin III deficiency. Incidence and clinical features.

Antithrombin III (ATIII) deficiency is inherited as an autosomal dominant trait. Three types of ATIII deficiency are recognized clinically. The prevalence of ATIII deficiency is uncertain; it has been estimated to occur in between one in 2,000 and one in 20,000 subjects. ATIII deficiency is found in between 4 and 6 percent of young patients with venous thrombosis, similar to but slightly lower than the prevalence of protein C and protein S deficiency in young subjects with thrombosis. The chances of finding a deficiency is increased if there is a history of familial or recurrent venous thrombosis. Cross-sectional reports in the literature are that between 30 and 80 percent of carriers have thrombosis. Thrombosis is uncommon in the first decade, but the risk rises sharply between the ages of 15 and 30. The major clinical manifestations of ATIII deficiency are young age at onset, idiopathic thrombosis, family history, and recurrent venous thromboembolism. Pregnancy and surgery are predisposing factors. Approaches to prophylaxis and treatment are discussed.

Adult↗
PubMed1989

Risks to the fetus of anticoagulant therapy during pregnancy.

The use of anticoagulants during pregnancy is problematic because of the potential adverse effects to the mother and the fetus. Heparin does not cross the placenta, and thus, it was surprising that a recent report concluded that heparin therapy during pregnancy was as risky as oral anticoagulant therapy. Therefore, we performed a literature review of fetal/infant outcomes following anticoagulant therapy during pregnancy. We examined 186 reports which described fetal/infant outcomes in 1,325 pregnancies associated with anticoagulant therapy. The rates of adverse fetal/infant outcomes including death, prematurity and cogenital malformations following treatment with heparin, oral anticoagulants, or both were calculated. The previously described high rate of adverse fetal/infant outcomes with heparin-treated patients, could be accounted for by the frequent use of heparin in pregnancies with comorbid conditions independently associated with adverse outcomes and by reports of uncomplicated prematurity. After excluding such pregnancies, outcomes in heparin-treated patients are similar to the normal population.

Anticoagulants↗
PubMed1989

Risks to the fetus of radiologic procedures used in the diagnosis of maternal venous thromboembolic disease.

The diagnosis of suspected venous thromboembolic disease during pregnancy is problematic because of the fear of fetal irradiation with routine diagnostic procedures. In order to develop rational guidelines, we have calculated levels of radiation exposure to the fetus for the common diagnostic procedures and conducted a literature review to examine the fetal risks associated with these levels of radiation. A small increase in the relative risk of childhood cancer is suggested by a literature review of outcomes following low dose (less than 5 rads), in utero radiation exposure. With careful use of the available procedures, a diagnosis of venous thrombosis is possible with fetal radiation exposure of less than 0.50 rads and a diagnosis of pulmonary embolism is possible with fetal radiation exposure of less than 0.05 rads. The risk of such exposure is small, both in relative and absolute terms.

Female↗
PubMed1989

Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction.

We performed a double-blind randomized trial comparing high doses of subcutaneous heparin (12,500 units every 12 hours) with low doses (5000 units every 12 hours) for 10 days in the prevention of left ventricular mural thrombosis in 221 patients with acute anterior myocardial infarction. Left ventricular mural thrombosis was observed by two-dimensional echocardiography on the 10th day after infarction in 10 of 95 patients (11 percent) in the high-dose group and in 28 of 88 patients (32 percent) in the low-dose group (P = 0.0004). One patient in the high-dose group and four in the low-dose group had nonhemorrhagic strokes (P = 0.17). One patient in the low-dose group had a fatal pulmonary embolism. There was no difference in the frequency of hemorrhagic complications, which occurred in six patients in the high-dose group and four in the low-dose group. The mean (+/- SEM) plasma heparin concentration was 0.18 +/- 0.017 U per milliliter in the high-dose group and 0.01 +/- 0.005 U per milliliter in the low-dose group (P less than 0.0001). In the high-dose group, the mean plasma heparin concentration was 0.10 +/- 0.029 U per milliliter among patients with abnormal two-dimensional echocardiograms, as compared with 0.19 +/- 0.019 U per milliliter among patients with normal echocardiograms (P = 0.01). We conclude that heparin administered subcutaneously in a dosage of 12,500 units every 12 hours to patients with acute anterior transmural myocardial infarction is more effective than a lower dosage (5000 units every 12 hours) in preventing left ventricular mural thrombosis.

Aged↗
PubMed1989

Unfractionated heparin inhibits thrombin-catalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa.

We have proposed previously that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent amplification reactions, and that prothrombinase is formed in heparinized plasma only after Factor Xa activates Factor VIII and Factor V. These propositions were based on the demonstration that both heparin and Phe-Pro-Arg-CH2Cl completely inhibited 125I-prothrombin activation for up to 60 s when contact-activated plasma (CAP) was replenished with Ca2+. Furthermore, the addition of thrombin to CAP before heparin or Phe-Pro-Arg-CH2Cl completely reversed their inhibitory effects. Additional support for the above hypotheses is provided in this study by demonstrating that, when the activity of thrombin is suppressed by heparin (indirectly) or by Phe-Pro-Arg-CH2Cl (directly), exogenous Factor Xa reverses the ability of these two agents to inhibit prothrombin activation. Prothrombin activation was initiated by adding Factor Xa (1 nM) or thrombin (1 or 10 nM) simultaneously with CaCl2 to CAP. In the absence of heparin or Phe-Pro-Arg-CH2Cl, prothrombin activation was seen 15 s later in either case. Heparin failed to delay, and Phe-Pro-Arg-CH2Cl delayed for 15 s, prothrombin activation in CAP supplemented with Factor Xa. In contrast, heparin and Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation for at least 45 s in CAP supplemented with 1 nM-thrombin. Heparin failed to delay prothrombin activation in CAP supplemented with 10 nM-thrombin, whereas Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation in this plasma for 45 s. These results suggest that in CAP: (1) Factor Xa can effectively activate Factor VIII and Factor V when the proteolytic activity of thrombin is suppressed; (2) heparin-antithrombin III is less able to inhibit Factor Xa than thrombin; (3) suppression of the thrombin-dependent amplification reactions is the primary anticoagulant effect of heparin.

Antithrombin III↗
PubMed1989

Molecular genetics of dopa decarboxylase and biogenic amines in Drosophila.

The gene Ddc encodes two isoforms of the enzyme dopa decarboxylase in Drosophila. These gene products catalyze the final steps in the synthesis of the biogenic amines serotonin and dopamine. This article summarizes recent progress in understanding the tissue- and cell-specific regulation of Ddc, which occurs at both the transcription and alternate splicing levels. In addition, results that are pertinent to understanding the roles of biogenic amines in the neurophysiology of Drosophila are discussed.

Animals↗
PubMed1989

Special report: a simple system for the derivation of International Normalized Ratios for the reporting of prothrombin time results with North American thromboplastin reagents.

The World Health Organization international scale of reporting prothrombin time results is based on the calibration of thromboplastins against an international reference preparation to derive an International Sensitivity Index (ISI). Once the ISI has been assigned to an individual thromboplastin reagent, the derivation of International Normalised Ratios (INRs) for reporting results depends on mathematic formulae requiring a special calculator or mathematic tables. This causes difficulties and errors. A simplified system for interpretation of INRs with the range of thromboplastins widely used in North America is therefore presented, which obviates the need for mathematic procedures for the derivation of INR equivalents. It should thus facilitate the application of the INR system and of safer therapeutic ranges.

Calibration↗
PubMed1989

A neuron-specific enhancer of the Drosophila dopa decarboxylase gene.

At least two cis-regulatory elements are necessary for correct neuron-specific expression of the Drosophila melanogaster dopa decarboxylase gene, Ddc. In addition to a previously described proximal element located approximately 60 bp upstream of the mRNA start site, we have now characterized a distal approximately 600-bp DNA fragment, extending from -1019 to -1623 bp, which possesses enhancer-like properties and is essential for normal neuron-specific expression. Immunofluorescent labeling of neurons expressing deleted Ddc genes indicates that this region contains both general neuronal regulatory elements and cell-specific elements that selectively affect Ddc expression in either dopaminergic or serotonergic neurons. These selective effects can be correlated with the removal of sequence elements that are protected from DNase digestion by factors present in embryonic nuclear extracts. Several of these elements are also homologous to sequences located upstream of the evolutionarily diverged Ddc gene of Drosophila virilis. These results suggest that the neuron-specific expression of Ddc results from the combined action of several factors binding within this distal enhancer region.

Animals↗
PubMed1989

Embryonic expression pattern of a family of Drosophila proteins that interact with a central nervous system regulatory element.

The protein Elf-1 interacts with a cis-acting element that is required specifically for the neuronal expression of the Drosophila dopa decarboxylase gene Ddc. Using protein purified from Drosophila embryos, we raised Elf-1-specific monoclonal antibodies. The expression of Elf-1 during embryogenesis is restricted to nuclei of tissues derived from ectoderm, predominantly the central nervous system (CNS) and the epidermis. Within the CNS, Elf-1 is present in only a small fraction of nuclei, and the pattern of expressing nuclei changes dramatically during development. Elf-1 and Ddc are coexpressed in primary cultures of neural cells. However, we do not detect Elf-1 in Ddc-expressing neurons in vivo, leading to the suggestion that Elf-1 activity is required in vivo for initiation of Ddc expression but not for its maintenance. The antibodies also were used to isolate cDNA clones encoding Elf-1. Alternate forms of Elf-1 mRNA result in at least three protein isoforms.

Amino Acid Sequence↗