Prevention and treatment of adverse effects of corticosteroids in systemic lupus erythematosus

The therapy of deep venous thrombosis consists of several elements and depends on the localization, the age and the extent of the thrombus. This article discusses various types of initial therapy and long-term treatment of venous thromboembolism and also reviews future perspectives of pharmacological treatment. The initial treatment regimens comprise thrombolysis, thrombectomy, inferior vena cava filters and the anticoagulation with either unfractionated heparin or low molecular weight heparins. Various thrombin-inhibitors have been tested for initial treatment of thrombosis, however, further investigations of their efficacy, safety and cost-effectiveness will have to provide firm evidence on their superiority when compared to unfractionated or low molecular weight heparins.     

Heparin-induced thrombocytopenia with thrombotic complications during prophylactic treatment with low-molecular-weight heparin

Heparin-induced thrombocytopenia is very uncommon with low-molecular-weight heparin, especially when given for prophylaxis of venous thromboembolism. In two of the four published cases, with thrombotic complications, thrombocytopenia may have been related to cross-reactivity between unfractionated heparin and low-molecular-weight heparin. We report one patient who received low-molecular-weight heparin for prophylaxis against venous thromboembolism without any previous injection of unfractionated heparin, and experienced thrombocytopenia with thrombotic complications. Heparin-induced thrombocytopenia was confirmed by several laboratory assays. This observation emphasizes the need for platelet count monitoring during low-molecular-weight heparin therapy.     

Venous thromboembolism in multiple trauma patients

Thromboembolic complications are frequent in patients with multiple trauma. The efficacy of unfractionated heparin for venous thrombosis prophylaxis has not been established. Based on limited prospective data, low-molecular-weight heparin appears to be more effective than unfractionated heparin and at least as effective as compression devices for preventing thromboembolic complications in these patients. Vena cava filters should be considered in high-risk patients who cannot receive anticoagulant therapy, but long-term filter use without concomitant anticoagulant therapy is associated with a substantial risk of recurrent thromboembolism.     

Heparin therapy in pediatric patients

Advances in tertiary care pediatrics have resulted in heparin being one of the most frequently prescribed drugs in children's hospitals. Heparin is essential for cardiopulmonary bypass, extracorporeal membrane oxygenation, renal dialyses, maintenance of patency of venous and arterial catheters, and treatment of thromboembolic events. Currently, protocols validated in adults are used for children. However, optimal use of heparin in pediatric patients will likely differ from adults because of age-dependent physiologic and pathologic differences in hemostasis that influence the activities of heparin. The following review summarizes the influence of age on heparin anticoagulant activities, and pharmacokinetics. The indications, monitoring, therapeutic range, factors influencing dose-response relationships, and side effects of heparin therapy in pediatric patients are discussed. Finally the current and future indications for low-molecular-weight heparins in pediatric patients are summarized. Multi-centered, international clinical trials are urgently needed to assess and optimize the use of heparin in pediatric patients in a variety of clinical settings. Until these studies are completed, recommendations for adults provide guidelines for children.     

Abbreviated hospitalization for deep venous thrombosis with the use of ardeparin

BACKGROUND: Ardeparin sodium has recently received approval by the Food and Drug Administration for prophylaxis against venous thromboembolism in patients undergoing elective total knee replacement. However, this low-molecular-weight heparin has not been previously evaluated in a randomized controlled trial for treatment of established acute deep venous thrombosis. METHODS: The study included patients with ultrasound-documented acute symptomatic deep venous thrombosis of the legs. They had to be deemed appropriate for discharge home to receive subcutaneous low-molecular-weight heparin. Patients were randomized to receive ardeparin with a 2-day hospitalization or unfractionated heparin sodium with a 5-day hospitalization. Both groups received warfarin sodium. Follow-up ultrasound examinations were undertaken at 6 weeks. RESULTS: Of the 80 patients enrolled, 75 had follow-up ultrasonography. Evaluation of baseline vs 6-week venous scans demonstrated that, overall, 31 of the 39 ardeparin-treated patients improved, compared with 21 of the 36 patients assigned to receive unfractionated heparin (P=.05). The 95% confidence interval for the difference in improvement was 0.6% to 42% in favor of ardeparin. Median charges for ardeparin and unfractionated heparin were $2815 and $6500, respectively (P<.001). There were no differences in bleeding or patient satisfaction between the 2 groups. CONCLUSIONS: The results of this small preliminary trial suggest that ardeparin can be administered effectively and safely to selected patients with acute deep venous thrombosis and that, with proper nursing and home services, it can help decrease the duration of hospitalization.     

Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin

Low molecular weight heparins are used extensively for thromboprophylaxis. The aim of this study was to compare the activity of the low molecular weight heparin, enoxaparin, 20 mg and 40 mg, given once per day with unfractionated heparin, 7500iu given twice per day, in terms of their anti-Xa activity in puerperal women following caesarean section and with an additional risk factor for venous thromboembolism. Seventeen women were randomised to receive one of the three treatments. The anti-Xa activity associated with each treatment was measured prior to treatment and at 2, 4, 6, 12 and 24 hours. The mean anti-Xa values of the groups receiving enoxaparin, 20 mg and 40 mg, were significantly higher than those of the group receiving unfractionated heparin. There was no difference between the two enoxaparin groups in terms of the anti-Xa activity profiles. This study suggests that the use of enoxaparin is superior to unfractionated heparin in terms of anti-Xa activity.     

Low-molecular-weight heparins in the treatment of deep-vein thrombosis

OBJECTIVE: To compare the characteristics and clinical efficacy of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) in the treatment of deep-vein thrombosis (DVT). Adverse effects, dosing, and cost issues are also discussed. DATA SOURCES: A MEDLINE search (January 1984-October 1997) was used to identify pertinent French and English literature, including clinical trials and reviews on LMWHs and their use in DVT. STUDY SELECTION: Trials comparing dalteparin, enoxaparin, tinzaparin, and nadroparin with UFH were selected. As studies were numerous, only randomized trials including more than 50 patients were reviewed. Moreover, all patients studied had a first episode of symptomatic DVT confirmed by objective tests (i.e., venography, duplex ultrasonography, impedance plethysmography). Clinical efficacy and safety of LMWHs were assessed in these trials. DATA EXTRACTION: Results pertaining to venographic assessment, recurrent thromboembolism, total mortality, and bleeding complications were extracted from the selected studies. DATA SYNTHESIS: Compared with UFH, LMWHs have a longer plasma half-life, better subcutaneous bioavailability, more predictable anticoagulant response, and require less intense laboratory monitoring. Most trials demonstrate comparable effects on thrombus extension and incidence of recurrent thromboembolism. Compared with UFH, LMWHs do not alter total mortality. Although animal trials predict a lower hemorrhagic potential for LMWHs, the incidence of bleeding complications is generally similar to that observed with UFH. Outpatient management of DVT with LMWHs has shown comparable safety and efficacy with inpatient UFH use but a shorter hospital stay. CONCLUSIONS: Because LMWHs are as safe and as effective as UFH, and because of their more convenient method of administration, they can be considered valuable alternatives for the treatment of DVT. Savings generated by less intensive laboratory monitoring and the possibility of early hospital discharge and outpatient therapy may outweight the higher acquisition cost of LMWHs.     

Preventive treatment in internal medicine by low-molecular-weight heparin (nadroparine calcium)

On the basis of literature data the authors discuss the preventive treatment of the low-molecular-weight heparin in various non-surgical disorders. The method was compared with unfractionated heparin in the treatment of 20 high risk patients. The efficacy of the two different heparins was examined on the liver and renal function, blood lipids and the hematologic and hemostaseologic parameters. The thromboembolic and hemorrhagic complications were observed. Significant difference was not found with the comparison of the two preparations. The authors emphasize the simplicity, safety, home treatment possibility of the low-molecular-weight heparin and the regular control of thrombocyte-count only, too.     

Danaparoid in the prevention of thromboembolic complications

OBJECTIVE: To review the therapies used to prevent postoperative thromboembolic complications with a focus on the role of danaparoid, a new low-molecular-weight glycosaminoglycan. DATA SOURCES: A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms included danaparoid, heparinoid, lomoparin, heparin, prophylaxis, thrombosis, embolism, thromboembolism, and thromboembolic and postoperative complications. The manufacturer of danaparoid was contracted for additional information related to this compound. STUDY SELECTION AND DATA EXTRACTION: All identified articles were reviewed for possible inclusion in this review. Comparisons primarily focused on data obtained from prospective, randomized, controlled, blind clinical trials. Another important consideration was the use of venography to determine the presence of deep venous thrombosis. DATA SYNTHESIS: Various therapies are available for the prevention of postoperative thromboembolic complications. Effective pharmacologic treatments currently available include adjusted-dose heparin, warfarin, aspirin, dextran, and low-molecular-weight heparins (LMWHs). Until recently, warfarin was considered the drug of choice for thromboprophylaxis in high-risk patients, including patients undergoing orthopedic surgical procedures. Because of their comparable efficacy and greater ease of use, LMWHs are gaining favor over warfarin in this patient population. In well-designed clinical trials involving patients undergoing elective total hip replacement or fractured hip surgery, danaparoid has demonstrated greater efficacy than other active treatments, including warfarin, dextran, aspirin, and heparin plus dihydroergotamine. While studies comparing danaparoid with LMWHs have not yet been published, danaparoid may be more useful in patients with heparin-associated thrombocytopenia. CONCLUSIONS: Danaparoid is an antithrombotic agent with characteristics that distinguish it from heparin and LMWHs. Based on the efficacy and safety data reviewed, danaparoid should be considered one of the drugs of choice for the prevention of thromboembolic complications in patients undergoing orthopedic hip procedures and the drug of choice for the management of any patient with heparin-induced thrombocytopenia who requires anticoagulant therapy.     

Low molecular weight heparins in special populations

Low molecular weight heparins (LMWH) are replacing unfractionated heparin (UH) as safe and effective agents for the prevention and treatment of thromboembolism. Although LMWH offer many advantages over UH, usage is less clearly defined in certain special populations, including renal dysfunction, obesity and pregnancy. This article will briefly review the pharmacology of LMWH and discuss usage in these special populations.     

A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group

BACKGROUND: The efficacy and safety of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis is still a matter of debate. METHODS: Using a two-by-two factorial design, we randomly assigned 400 patients with proximal deep-vein thrombosis who were at risk for pulmonary embolism to receive a vena caval filter (200 patients) or no filter (200 patients), and to receive low-molecular-weight heparin (enoxaparin, 195 patients) or unfractionated heparin (205 patients). The rates of recurrent venous thromboembolism, death, and major bleeding were analyzed at day 12 and at two years. RESULTS: At day 12, two patients assigned to receive filters (1.1 percent), as compared with nine patients assigned to receive no filters (4.8 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.22; 95 percent confidence interval, 0.05 to 0.90). At two years, 37 patients assigned to the filter group (20.8 percent), as compared with 21 patients assigned to the no-filter group (11.6 percent), had had recurrent deep-vein thrombosis (odds ratio, 1.87; 95 percent confidence interval, 1.10 to 3.20). There were no significant differences in mortality or the other outcomes. At day 12, three patients assigned to low-molecular-weight heparin (1.6 percent), as compared with eight patients assigned to unfractionated heparin (4.2 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.38; 95 percent confidence interval, 0.10 to 1.38). CONCLUSIONS: In high-risk patients with proximal deep-vein thrombosis, the initial beneficial effect of vena caval filters for the prevention of pulmonary embolism was counterbalanced by an excess of recurrent deep-vein thrombosis, without any difference in mortality. Our data also confirmed that low-molecular-weight heparin was as effective and safe as unfractionated heparin for the prevention of pulmonary embolism.     

Anticoagulants for venous thrombosis

The anticoagulant agents heparin and warfarin were introduced before the era of randomised clinical trials. As a result, the indications, dosages and monitoring techniques of these drugs have undergone re-evaluation in multiple clinical trials in the past years. Low molecular weight heparin has been developed, which has led to new approaches in anticoagulant management. Current levels of laboratory, pharmacology and clinical knowledge in the treatment of venous thromboembolism are discussed.     

Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis

BACKGROUND: Randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Recently, some authors reported a pooled analysis of selected studies in the literature that suggested that there is no convincing evidence that the risk of recurrent venous thromboembolism is critically dependent on achieving a therapeutic activated partial thromboplastin time result at 24 to 48 hours. METHODS: We provide the analyses of patient groups entered into our series of 3 consecutive double-blind randomized trials evaluating initial heparin therapy for proximal deep venous thrombosis. RESULTS: Logistic regression analysis of the patient groups receiving the less intense initial intravenous heparin dose of 30,000 U/24 h demonstrated that subtherapy for 24 hours predicted the onset of venous thromboembolic events. Failure to achieve a therapeutic activated partial thromboplastin time by 24 hours was associated with a 23.3% frequency of venous thromboembolism vs 4% to 6% for those whose activated partial thromboplastin time exceeded the therapeutic threshold by 24 hours (P=.02). Time-to-event analysis shows the increased frequency of recurrent venous thromboembolic events during the period of study in patients who were subtherapeutic for 24 hours compared with those who were therapeutic (P=.001). CONCLUSIONS: Our findings reaffirm the clinical importance of rapidly achieving therapeutic levels of heparin. Patients who failed to achieve the therapeutic threshold by 24 hours were at an increased risk of subsequent recurrent venous thromboembolism. These findings are independently supported by the results of a randomized trial comparing different intensities of initial heparin treatment by continuous infusion.     

Treatment of venous thromboembolism

There have been some important advances in the treatment of venous thromboembolism during the past 18 months. A randomized trial has confirmed earlier observations indicating an adequate initial heparin effect is required to prevent recurrent venous thromboembolism, and it is critical to achieve this effect within the first 24 hours of therapy. The need to use a validated protocol for administering intravenous heparin is now firmly established. The clinician has a choice between two protocols that have been validated by randomized trials and provide both effective and safe heparin therapy. For patients with clinically suspected pulmonary embolism, the clinician now has a practical noninvasive strategy that avoids pulmonary angiography, identifies patients with proximal-vein thrombosis who require treatment, and avoids the need for treatment and further investigation in the majority of patients.     

Low molecular weight heparins. Implications in anesthesia and resuscitation

Low molecular weight heparins are a group of drugs that have only recently been introduced in clinical practice. The are widely used for prophylaxis in thromboembolic disease and are being employed increasingly to treat established venous thrombosis. One way in which these drugs are often used is for prophylaxis in the perioperative period for patients at high risk of developing venous thromboembolism, and the anesthesiologist must therefore be familiar with the main aspects of this application. We review pharmacological characteristics of these drugs as well as the literature on low molecular weight heparins, stressing points of main interest to the anesthesiologist and intensive care recovery unit specialist, namely adverse effects (mainly bleeding) and the implications that use of low molecular weight heparin will have on choice of anesthetic (in particular the dilemma of whether to use local/regional anesthesia).     

The phenylalanyl-tRNA synthetase specifically binds DNA

BACKGROUND: Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation. METHODS: Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens. RESULTS: Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively. CONCLUSIONS: A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.     

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents

The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands. L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units. We now show that these HS chains can also bind P-selectin, but not E-selectin. However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent. Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations. Porcine intestinal mucosal (mast cell-derived) heparin (PIM-heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations. Analysis of defined heparin fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns. L-selectin binding fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups. The P-selectin binding component includes this fraction as well as some less highly modified regions. Thus, endothelium-derived HS chains and mast cell-derived heparins could play a role in modulating the biology of selectins in vivo. Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo. In contrast, two low molecular weight heparins currently considered as clinical replacements for unfractionated heparin are much poorer inhibitors. Thus, patients undergoing heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight heparins may come at some loss of this effect. Low-dose unfractionated heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles.     

Treatment of venous thromboembolism

This review provides meta-analytic data of studies aiming at improved treatment of deep vein thrombosis and pulmonary embolism. The introduction of low molecular weight heparin has considerably ameliorated the initial treatment of deep vein thrombosis, and should now be regarded as the treatment of choice for most patients with deep vein thrombosis. Oral anticoagulant treatment is presently considered safe and effective for the long-term treatment of venous thromboembolism, provided that the INR is maintained at 2.0-3.0. However, the optimal duration as well as the optimal intensity of anticoagulation have still to be determined. Patients with submassive pulmonary embolism should presently be treated with adjusted dose unfractionated heparin and coumarins. Studies determining the efficacy and safety of low molecular weight heparin in this condition deserve priority. Thrombolytic therapy should be restricted to patients with massive pulmonary embolism, unless safer methods of thrombolysis have been developed. Surgical embolectomy and catheter fragmentation of emboli seem alternative options but deserve further investigations.     

A counterdefensive strategy of plant viruses: suppression of posttranscriptional gene silencing

Anticoagulants have been used in patients with acute ischemic stroke to limit infarct volume and to prevent reinfarction and thrombotic complications like deep venous thrombosis. Three important randomized trials of anticoagulants have been reported recently. One trial showed that nadroparin reduced the percentage of patients with poor outcome at 6 months. One unblinded trial of subcutaneous unfractionated heparin showed that heparin reduced the rate of early recurrent stroke, but this benefit was offset by an increase in hemorrhages. A trial of the heparinoid ORG 10172 showed no efficacy overall at 3 months, although there was an increase in patients with very favorable outcomes at 7 days. The defibrinogenating agent ancrod has shown promise in a series of small clinical trials, but efficacy has not been established. There are no reliable data on the use of antithrombotic agents to prevent reocclusion after thrombolytic therapy. Anticoagulants are generally recommended in patients with cerebral venous thrombosis, but the recommendation is supported by only one small and methodologically limited trial.     

Low-molecular-weight heparins

Low-molecular-weight heparins (LMWH) are a new group of parenteral anticoagulants. They represent a major clinical advance in anticoagulation since the identification of unfractionated heparin (UFH) in 1922 and the introduction of the synthetic coumarin derivative, warfarin, in 1948. Their predictable pharmacokinetics, increased bioavailability, and longer plasma half-life allow for once- or twice-daily dosing and eliminate the need for routine laboratory monitoring. This simplified administration stands to alter the clinical practice of anticoagulation. This review high-lights recent clinical trials and focuses on studies comparing LMWH with the other two major anticoagulants: UFH and coumadin.