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.     

Self-blame and peer victimization in middle school: an attributional analysis

Intravenous heparin followed by warfarin has been the classical anticoagulant therapy of acute venous thromboembolism for the past 30 years. In recent years a number of low-molecular-weight heparins have become available for clinical trials. These agents have a number of advantages over unfractionated heparin and are now being used internationally for the prevention and treatment of venous thromboembolism. Low-molecular-weight heparin will undoubtedly replace intravenous unfractionated heparin not only in the treatment of venous thromboembolism but in other conditions where heparin therapy is indicated. Whether or not the low-molecular-weight heparins can decrease or eliminate some of the complications of unfractionated heparin will depend on the outcome of future clinical trials.     

Antibody-induced arterial thromboembolism resulting in amputation after total knee arthroplasty

Heparin-induced thrombocytopenia is a rare drug reaction that can be associated with thrombotic complications leading to myocardial infarct, stroke, or ischemic loss of a limb. Because of the broadening indications of low-molecular-weight heparin use, the current emphasis on ambulatory care, and the difficulty in clinical diagnosis and treatment of this drug reaction, heparin-induced thrombocytopenia is the most important allergic drug reaction that physicians must manage. An antibody-mediated drug reaction to low-molecular-weight heparin that resulted in a below-knee amputation after an elective total knee arthroplasty is reported.     

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.     

Preventing the cardiotoxic effects of anthracyclines with Cardioxane]

An immune response to heparin, which is clinically manifested by the development of thrombocytopenia with or without thrombosis, is stimulated by a complex of heparin with platelet factor 4 (PF4). The primary thrombotic events in patients with heparin-induced thrombocytopenia (HIT) are more frequently venous than arterial. The development of antibodies, however, does not always result in thrombocytopenia or in catastrophic events. The antibodies, which are of the IgG, IgM, and IgA isotypes, can be easily measured by an ELISA that contains a complex of heparin-platelet factor 4 (PF4). Initial antibody formation can be greatly reduced by limiting the exposure to unfractionated heparin or by the use of low-molecular-weight heparin. For those patients who require anticoagulation and who have antibodies to heparin-PF4, danaparoid (Orgaran), a low-molecular weight heparinoid that does not react with the antibodies, is now commercially available; argatroban, a thrombin-specific inhibitor, can also be obtained for compassionate use. The use of these agents during anticoagulation with warfarin is preferable to the simple discontinuation of heparin and intitiation of warfarin, because the latter treatment can result in ongoing thrombosis.     

Anticoagulant therapy with recombinant hirudin in patients with thrombopenia induced by heparin

OBJECTIVES: Heparin-induced thrombocytopenia is an uncommon and severe complication of heparin therapy. Both venous and arterial thromboembolic events can occur, requiring withdrawal of the heparin therapy. When anticoagulant therapy is mandatory, recombinant hirudin can be used. METHODS: We used recombinant hirudin (HBW 023) in 6 patients with heparin induced thrombocytopenia. In case of venous thromboembolism, an initial intravenous bolus (0.07 mg/kg) was followed by continuous infusion (0.05 mg/kg/h); for arterial thromboembolism the initial bolus was 0.7 mg/kg and infusion rate 0.15 mg/kg/h. When possible oral anticoagulants were started and hirudin withdrawn when the INR ratio reached 3. RESULTS: The clinical course was uneventful in all 6 patients. There was no recurrent thromboembolism. Cephalin-activated coagulation time (patient/control) varied between 1.8 and 3.5 (median 2.4) during hirudin administration. Platelet count rose to the nadir (median 70 x 10(9)/l, range 15-90) reaching over 100 x 10(9)/l in all patients between the third and sixth day (median 5 days) after stopping heparin. CONCLUSION: Intravenous administration of hirudin provides effective immediate anticoagulation in patients with heparin-induced thrombocytopenia, thus allowing conversion to oral anticoagulants without risking recurrent thromboembolism.     

Skin necrosis following subcutaneous heparin injection

Heparin-induced skin necrosis is a rare but serious complication of subcutaneously administered heparin. Previous reports indicate that the skin necrosis is often accompanied by thrombocytopenia and occasionally by lethal thromboembolism. It thus shows features similar to the heparin-induced thrombocytopenia (HIT) syndrome and probably represents a localized form of this condition. Caution is required in the event of skin necrosis; heparin therapy should be ceased immediately and not used again if the complications of HIT are to be avoided.     

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.     

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.     

Low-dose heparin thromboembolism prophylaxis

OBJECTIVE: To determine a rational approach to heparin dosing for thromboembolism prophylaxis. DESIGN: Literature review. RESULTS: Three commonly used heparin dosing regimens were identified: (1) standard low-dose heparin (5000 U administered subcutaneously 2-3 times per day); (2) adjusted-dose heparin (adequate to elevate the activated partial thromboplastin time to 5 seconds above the upper limit of normal); and (3) low-molecular-weight heparin (30 mg subcutaneously twice daily without monitoring). CONCLUSIONS: Adjusted-dose heparin thromboembolism prophylaxis is both the safest and most reliable method currently available.     

Heparin-induced thrombocytopenia: new insights into the impact of the FcgammaRIIa-R-H131 polymorphism

Heparin-induced thrombocytopenia (HIT), a severe complication of heparin treatment, can be associated with new thrombotic complications. HIT antibodies activate platelets via the platelet Fcgamma-receptor (FcgammaRIIa), which carries a functionally relevant polymorphism (FcgammaRIIa-R-H131). The effect of this polymorphism on the clinical manifestations of HIT is controversial. We determined prospectively the FcgammaRIIa-R-H131 genotypes in 389 HIT patients, in 351 patients with thrombocytopenia or thrombosis due to causes other than HIT and without detectable HIT antibodies, and in 256 healthy blood donors. For this purpose, a novel nested sequence-specific primer-polymerase chain reaction (SSP-PCR) was developed. FcgammaRIIa-R/R131 was found to be overrepresented in the HIT patients (27%) compared with the control groups (non-HIT patients [21%] and blood donors [20%]). In a subgroup of 122 well-characterized HIT patients, the genotype distribution in patients presenting with thrombocytopenia only was compared with that of patients who developed thromboembolic complications. The frequency of FcgammaRIIa-R/R131 among patients with thrombotic events was significantly elevated (37% v 17%; P = .036). Our results indicate that genotype distribution can be correlated to the clinical outcome of patients with HIT. We speculate that the reduced clearance of immune complexes in patients with the FcgammaRIIa-R/R131 allotype causes prolonged activation of endothelial cells and platelets, thus increasing the risk for thrombotic complications.     

The influence of cytomegalovirus on the natural history of HIV infection: evidence of rapid course of HIV infection in HIV-positive patients infected with cytomegalovirus

PROBLEM: A life-threatening complication of the thrombembolism prophylaxis with heparin is heparin-induced thrombocytopenia (HIT) type II. HIT type II is based on immunological mechanisms. Even low, subcutaneously applied doses may produce HIT type II. In those patients, continued application may cause thromboembolic complications. The most important symptom of HIT type II is a decrease of platelets. METHODS: In a prospective study, we investigated the incidence of HIT type II within the period from 01.07.95 to 30.06.96 in orthopedic patients. We also evaluated the importance of the daily platelet count from the fifth postoperative day for the early diagnosis of HIT type II and a possible reduction of the thrombosis rate. The study included 307 patients after primary implantation of hip and knee endoprosthesis and after hip endoprosthesis replacement. All patients received 3 x 5000 IU/d of unfractionated heparin subcutaneously. Whenever there was a decrease of platelets of at least 50% in relation to the preoperative value or whenever thrombembolic complications occurred, serum was analyzed by the heparin-induced platelet activation test (HIPA). RESULTS: 20 patients developed HIT type II. This corresponds to an incidence of 6.5%. 10 of the HIT type II antibody positive patients (50%) developed thrombembolic complications. 3 patients (0.9%) of the group studied developed clinically symptomatic thrombembolic complications without evidence of heparin antibodies. The total risk of getting thrombembolic complications was 4.2% (13 patients). 3.3% (10 patients) of the entire group developed HIT type II antibody associated thrombembolic complications; 1 patient died. The lethality in the HIT type II antibody positive patient group amounted to 5%. The patients with HIT type II received LMW heparinoid Orgaran (AKZO-Organon, The Netherlands) or hirudin (as a clinical trial). The comparison group (retrospective study from 17.10.92 to 16.10.93) was composed of 262 patients with the same operations and equal thromboembolism prophylaxis. The platelet count was made only as part of routine diagnostic tests. 21 patients (8.0%) developed clinically symptomatic thrombembolic complications. The difference in the thrombosis rate between these two groups of patients is statistically significant. Unrecognized HIT type II is probably the reason for the high thrombembolic complication rate in the comparison group. CONCLUSIONS: The daily platelet count from the fifth postoperative day and from the first day in case of reexposure to heparin is an important measure for the early diagnosis of HIT type II.     

Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.     

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.     

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.     

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.     

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.     

Subcutaneous low-molecular-weight heparin for treatment of Trousseau's syndrome

We report the case of a 76-year-old man with recurrent thromboses despite oral anticoagulation with phenprocoumon and low-grade chronic disseminated intravascular coagulation. Workup revealed a bronchial carcinoma (NSCCL) with hilar and mediastinal lymph node metastases. The clinical condition was consistent with Trousseau's syndrome. Based on reports in the literature, the therapy was changed to intravenous unfractionated heparin (UFH), which was effective in controlling the thrombotic coagulopathy. For practical reasons, despite a lack of evidence of its effectiveness in Trousseau's syndrome, therapy with UFH was changed to subcutaneous low-molecular-weight heparin (LMWH, nadroparine) in therapeutic doses of 100 IU/ kg body wt. 12 hourly. On an outpatient basis, five chemotherapy cycles were administered, and after metastases of the brain had been detected radiotherapy was initiated. Following 7.5 months of progressive neoplastic disease the patient died. He had remained free of thromboembolic complications under continued LMWH therapy during the last 6.5 months of his life. LMWH might be a convenient alternative to the established therapy with UFH in Trousseau's syndrome.     

Low molecular weight heparin: a critical analysis of clinical trials

LMWHs are an important new class of antithrombotic agents. They differ from UFH in having relatively more anti-Xa activity, greater bioavailability at low doses, longer half-life, and more predictable anticoagulant response when administered in fixed doses. These properties allow LMWHs to be administered QD or at most BID and without laboratory monitoring. The incidence of heparin-induced thrombocytopenia also appears to be lower with an LMWH than with heparin. Given their favorable pharmacological profile, it was of interest to critically appraise clinical trials of thromboprophylaxis and treatment with these new agents. In orthopedic trials, it was noted that LMWH provided safe and effective thromboprophylaxis for patients undergoing major orthopedic surgery of the lower limb. In those having hip arthroplasty, LMWH was as effective as low-intensity warfarin therapy, but its use was associated with more wound hematomas. In those having total knee arthroplasty, LMWH was more effective than warfarin and did not increase bleeding. However, the prevalence of DVTs complicating this procedure as well as acute hip fracture remains unacceptably high, and additional studies of LMWH in combination with other prophylactic methods, such as external pneumatic compression, are needed. Only one adequately designed trial found less bleeding resulted from LMWH prophylaxis administered at an equivalent antithrombotic dose to UFH. In general medical patients, LMWH appeared to be as effective as UFH and had the advantages of less frequent injections and fewer injection site hematomas. In general surgical patients, there was a lower risk of thromboembolism but a trend toward an increase in bleeding events. Subjects with strokes and spinal cord injuries benefited from fewer thrombotic events, and the latter had fewer bleeding complications. Other potential indications for LMWH, such as cardiopulmonary bypass, hemodialysis, and preservation of graft patency, are presently under study. Perhaps the most impressive benefits of LMWH will be realized when it is used for the treatment of venous thromboembolism. The meta-analysis presented in this review showed a trend toward greater efficacy with LMWH and fewer major bleeding events in comparison with adjusted-dose intravenous UFH. Also, during the months following the thrombotic event, there was significantly less mortality in patients receiving LMWH. A further advantage was the subcutaneous route of administration and lack of requirement for laboratory monitoring. Additional treatment trials are presently in progress and may establish LMWH as the treatment of choice for patients with thromboembolic disorders.     

Hereditary antithrombin deficiency and pregnancy. Pregnancy course in six women with known hereditary antithrombin deficiency

Inherited antithrombin (AT) deficiency is a major cause of venous thromboembolism, especially in relation to surgery and pregnancy. We present six AT deficient pregnant women, who successfully delivered seven babies at the Department of Gynaecology/Obstetrics, Aalborg Hospital. From conception, or if possible prior to conception, the women were treated with unfractionated (UFH) or low molecular weight heparin (LMWH) throughout the pregnancy. If the pregnancy was without complication, AT substitution was only used at delivery and for approximately a week post-partum, when warfarin treatment was re-instituted.