Does the type of hormone replacement therapy influence the risk of deep vein thrombosis? A prospective case-control study.

BACKGROUND: Although hormone replacement therapy (HRT) is associated with an increased risk of deep vein thrombosis (DVT), it is not clear if the risk differs in users of combined estrogen-progestin HRT and estrogen-only HRT. METHODS: We prospectively studied postmenopausal women with suspected DVT in whom HRT use status was ascertained and who subsequently had objective diagnostic testing to confirm or exclude DVT. Cases were patients with idiopathic DVT, in whom there were no DVT risk factors, and controls were patients without DVT, in whom there were also no DVT risk factors. The risk of DVT was determined in users of estrogen-progestin HRT and estrogen-only HRT by comparing the prevalence of current HRT use in cases with idiopathic DVT and controls without DVT (reference group). Multivariable regression analysis was done to adjust for factors that might confound an association between HRT use and the risk of DVT. RESULTS: One thousand one hundred and sixty-eight postmenopausal women with suspected DVT were assessed, from whom 95 cases of idiopathic DVT and 610 controls without DVT and no DVT risk factors were identified. Estrogen-only HRT was associated with an increased risk for DVT that was not statistically significant [odds ratio (OR) = 1.22; 95% confidence interval (CI) 0.57, 2.61]. Estrogen-progestin HRT was associated with a greater than 2-fold increased risk for DVT (OR = 2.70; 95% CI 1.44, 5.07). CONCLUSION: The risk of developing DVT may be higher in users of combined estrogen-progestin HRT than in users of estrogen-only HRT.

Once versus twice daily LMWH for the initial treatment of venous thromboembolism.

BACKGROUND: In the initial treatment of venous thromboembolism (VTE) low molecular weight heparin (LMWH) is administered once or twice daily. A once daily treatment regimen is more convenient for the patient and may optimise home treatment. However, it is not clear whether a once daily treatment regimen is as safe and effective as a twice daily treatment regimen. OBJECTIVES: To compare the efficacy and safety of once daily versus twice daily administration of LMWH. SEARCH STRATEGY: We identified trials through searching the Specialised Register of the Cochrane Peripheral Vascular Diseases Group (last searched April 2005), the Cochrane Central Controlled Trials Register (CENTRAL) (last searched Issue 2, 2005), handsearches of relevant journals, checking cross-references and through personal communication with experts. SELECTION CRITERIA: Randomised clinical trials in which LMWH given once daily is compared to LMWH given twice daily for the initial treatment of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Five studies were included with a total of 1508 participants. The pooled data showed a statistically non-significant difference in recurrent venous thromboembolism between the two treatment regimens (OR 0.82, 0.49 to 1.39). A comparison of major haemorrhagic events (OR 0.77, 0.40 to 1.45) and mortality (OR 1.14, 0.62 to 2.08) also showed a statistically non-significant difference between the two treatment regimens. AUTHORS' CONCLUSIONS: Once daily treatment with LMWH is as effective and safe as twice daily treatment with LMWH. However, the 95% confidence interval implies that there is a possibility that the risk of recurrent VTE might be higher when people are treated once daily. Hence, the decision to treat a person with a once daily regimen will depend on the evaluated balance between increased convenience and the potential for a lower efficacy.

Homocysteine and markers of coagulation and endothelial cell activation.

OBJECTIVES: In vitro studies suggest an influence of hyperhomocysteinemia on the coagulation system, but the influence of mild hyperhomocysteinemia in vivo is unclear. METHODS AND RESULTS: We studied the relation between homocysteine and markers of coagulation activation and endothelial cell activation in 279 patients with established atherosclerotic disease. In addition, we performed an investigator-blinded placebo-controlled cross-over study to investigate the influence of acute hyperhomocysteinemia by oral methionine load on these markers in 20 healthy volunteers. In the atherosclerotic patients prothrombin fragment F1+2 and soluble thrombomodulin (sTM) were associated with homocysteine in univariate analyses (P = 0.003 and P = 0.001, respectively), but not in multivariate analyses. Age, creatinine and MTHFR C677T polymorphism were major determinants of homocysteine concentration. MTHFR C677T polymorphism status was not associated with F1+2 and sTM. Median homocysteine concentrations increased in the healthy volunteers after methione load. However, after methionine load or after placebo, we did not observe different plasma concentrations of F1+2 (0.9 nmol L-1 vs. 0.9 nmol L-1, P = 0.39), d-dimer (153 micro g L-1 vs. 151 micro g L-1, P = 0.63) and von Willebrand factor (103% vs. 107%, P = 1.00). CONCLUSIONS: These results provide evidence against a major effect of mild hyperhomocysteinemia on activation of the coagulation system and endothelial cell activation in vivo.

Non-invasive diagnostic work-up of patients with clinically suspected pulmonary embolism; results of a management study.

BACKGROUND: Clinicians often deviate from the recommended algorithm for the diagnosis of pulmonary embolism consisting of ventilation-perfusion scintigraphy and pulmonary angiography. OBJECTIVES: To assess the safety and feasibility of a diagnostic algorithm which reduces the need for lung scintigraphy and avoids the use of angiography. PATIENTS AND METHODS: Consecutive patients with a clinical suspicion of pulmonary embolism were prospectively investigated according to an algorithm in which the diagnosis of pulmonary embolism was excluded after a low clinical probability estimate and a normal d-dimer test result, a normal perfusion scintigraphy result, or a non-high probability scintigraphy result in combination with normal serial ultrasonography of the legs. In these patients anticoagulant treatment was withheld and they were followed up for 3 months to record possible thromboembolic events. During the study period, 923 consecutive patients were seen, of whom 292 were excluded because of predefined criteria. RESULTS: Of the 631 included patients, the diagnosis was refuted on the basis of a low clinical probability estimate and a normal d-dimer test result (95 patients), normal perfusion scintigraphy (161 patients) and non-high probability lung scintigraphy followed by normal serial ultrasonography (210 patients). Of these 466 patients, venous thromboembolic complications during follow-up occurred in six (complication rate 1.3%, 95% confidence interval 0.5, 2.8). The diagnostic protocol was completed in 92% of all included patients. CONCLUSION: The diagnosis of pulmonary embolism can be safely ruled out by a non-invasive algorithm consisting of d-dimer testing combined with a clinical probability estimate, lung scintigraphy, or serial ultrasonography of the legs (in case of non-diagnostic lung scintigraphy).

Long-term thromboprophylaxis in practice: how can it be implemented?

Prolonging thromboprophylaxis after hospital discharge following surgery reduces the incidence of venographic and symptomatic venous thromboembolism (VTE), although the effects on post-thrombotic syndrome are not yet clear. Oral anticoagulants and low-molecular-weight heparins (LMWHs) may be used for extended outpatient therapy, but oral anticoagulants require frequent laboratory monitoring and may cause major gastrointestinal bleeding. Conversely, LMWHs are effective and safe at a fixed, once-daily dosage without monitoring. Four studies have shown that extended prophylaxis with LMWHs significantly reduces the incidence of post-discharge VTE following total hip replacement. However, the need for subcutaneous injection potentially limits home use of LMWHs outside clinical trials because the amount of drug administered may vary between injections if patients self-inject, while administration by nurses would be too costly. An auto-injection device is now available for administering the LMWH enoxaparin. The device is simple to use and delivers a precise pre-determined dose. During studies with such devices, volunteers successfully performed mock injections and patients with indications for thromboprophylaxis showed high levels of acceptance with administration for up to 3 weeks. Ongoing studies are assessing longer periods of self-administration.

Erythropoiesis and serum sVCAM-1 levels in adults with sickle cell disease.

Sickle cell patients are characterized by stress erythropoiesis involving cytokines, growth factors, and adhesion molecules. We set out to determine whether serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, which are inversely related to red blood cell counts in sickle cell disease (SCD), reflect erythropoietic activity in adult HbSS patients. Serum levels of sVCAM-1 were compared to erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and soluble transferrin receptor (sTfR) levels in 29 adults with HbSS, and their respective levels were also compared to 29 race- and age-matched HbAA controls. EPO and sTfR levels were increased as compared to healthy controls, whereas IL-3 and GM-CSF were not. No significant correlation of sVCAM-1 levels could be detected with any of the measured erythropoietic markers. Patients, but not controls, with detectable IL-3 levels had lower sTfR and GM-CSF levels as compared to patients with undetectable IL-3 levels. Even though a link of sVCAM-1 to erythropoiesis could not be established, it cannot be ruled out that sVCAM-1 levels reflect the release of young red blood cells into the circulation. IL-3 and GM-CSF levels suggest that different rates of erythropoiesis may be characterized by specific cytokine profiles in SCD. Further research should focus on the potential cytokines and adhesion molecules involved in sickle cell erythropoiesis, as this may increase our understanding of sickle cell complications and may provide us with potential markers for risk assessment in sickle cell disease as well.