| 1. |
- Berg, Cecilia, et al.
(author)
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Platelet-induced growth of human fibroblasts is associated with an increased expression of 5-lipoxygenase.
- 2006
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In: Thrombosis and haemostasis. - 0340-6245. ; 96:5, s. 652-9
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Journal article (peer-reviewed)abstract
- Proliferation of fibroblasts is vital for adequate wound healing but is probably also involved in different hyperproliferative disorders such as atherosclerosis and cancer. The regeneration of tissue usually starts with coagulation, involving release of mitogenic and inflammatory factors from activated platelets. This study focuses on the role of eicosanoids in the proliferative effects of platelets on human fibroblasts. We show that the phospholipase A (2) inhibitor 7,7-dimethyl-5,8-eicosadienoic acid (DMDA), the combined cyclooxygenase (COX) and lipoxygenase (LOX) inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) and the LOX inhibitor 5,8,11-eicosatriynoic acid (ETI) block the platelet-induced proliferation of serum starved subconfluent human fibroblasts. Anti-proliferative effects were also obtained by specific inhibition of 5-LOX with 5,6-dehydro arachidonic acid (5,6-dAA), whereas the 12-LOX inhibitor cinnamyl-3,4-dihydroxy- a -cyanocinnamate (CDC) did not affect the platelet-stimulated growth of fibroblasts. The expression of 5-LOX was analyzed by reverse-transcriptase-mediated PCR (RT-PCR), Western blotting and HPLC. 5-LOX message and protein was detected in fibroblasts but not in platelets. Incubation with platelets markedly increased, already after one hour, the expression of 5-LOX in the fibroblast culture. The increased 5-LOX activity was associated with an elevated level of the 5-LOX metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) reaching its maximum after 1 - 2 hours of co-incubation of fibroblasts and platelets. The 5-HETE production was reduced by the inhibitors DMDA, ETYA and ETI. In conclusion, this study suggests that platelet-stimulated proliferation of fibroblasts is mediated by an increased 5-LOX activity, which supports recent findings indicating a crucial role for this enzyme in proliferative disorders such as atherosclerosis.
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| 2. |
- Eriksson, Henry, 1946, et al.
(author)
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Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran
- 2005
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In: Thromb Haemost. - 0340-6245. ; 94:3, s. 522-7
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Journal article (peer-reviewed)abstract
- The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.
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| 3. |
- Fisher, W. D., et al.
(author)
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Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies
- 2007
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In: Thromb Haemost. - 0340-6245. ; 97:6, s. 931-7
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Journal article (peer-reviewed)abstract
- Rivaroxaban (BAY 59-7939) is an oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of venous thromboembolism (VTE). This analysis of pooled results from two phase II studies of rivaroxaban for VTE prevention after major orthopaedic surgery aimed to strengthen the conclusions of the individual studies. One study was conducted in patients undergoing total hip replacement (THR; N = 722), and one in patients undergoing total knee replacement (TKR; N = 621). In both studies, patients were randomized, doubleblind, to oral, twice-daily (bid) rivaroxaban beginning after surgery, or subcutaneous enoxaparin (40 mg once daily beginning before THR, and 30 mg bid beginning after TKR). Treatment continued until mandatory bilateral venography was performed 5-9 days after surgery. Total VTE (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 16.1-24.4% of per-protocol patients receiving rivaroxaban 5-60 mg, and 27.8% receiving enoxaparin (n = 914). There was a flat dose response relationship between rivaroxaban and total VTE (p = 0.39). Major bleeding (safety population, n = 1,317) increased dose-dependently with rivaroxaban (p < 0.001), occurring in 0.9%, 1.3%, 2.1%, 3.9%, and 7.0% of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60 mg, respectively, versus 1.7% of patients receiving enoxaparin. No routine coagulation monitoring was performed, and there were no significant differences between dose response relationships with rivaroxaban after THR and TKR. Overall, rivaroxaban total daily doses of 5-20 mg had the most favorable balance of efficacy and safety, relative to enoxaparin, for the prevention of VTE after major orthopaedic surgery.
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| 4. |
- Ogren, M., et al.
(author)
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Trousseau's syndrome - what is the evidence? A population-based autopsy study
- 2006
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In: Thromb Haemost. - 0340-6245. ; 95:3, s. 541-5
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Journal article (peer-reviewed)abstract
- Despite numerous studies documenting the association between cancer and venous thromboembolism (VTE), the reason for the excessive risk in certain cancers remains obscure. No large-scale studies have yet investigated the independent effects of cancer type, site and growth pattern. Between 1970 and 1982, 23,796 standardised autopsies were performed, representing 84% of all in-hospital deaths in an urban Swedish population. The relationship between cancer and PE was evaluated with logistic regression. The overall PE prevalence was 23%, and 10% of the population had a fatal PE. Forty-two per cent of pancreatic cancer patients had PE (OR 2.55; 95% CI 2.10-3.09) (p<0.001); gall bladder, gastric, colorectal and pulmonary adenocarcinomas were similarly independently associated with PE. In comparison with squamous cell lung cancer, patients with pulmonary adenocarcinoma had 1.65 times higher odds for PE (95% CI 1.20-2.29). Adenocarcinoma and metastatic cancer were independently associated with PE risk (OR 1.27; 95% CI 1.16-1.40; p<0.001, and OR 1.10;95% CI 1.01-1.20; p=0.024, respectively) but when controlling for cancer type and spread, pancreatic cancer was still associated with an OR of 2.10 (95% CI 1.71-2.58) of PE (p<0.001). We conclude that the risk of PE in cancer patients depends not only on the cancer site and spread but also on the histological type. The excess independent risk in pancreatic cancer is intriguing and should warrant further research.
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| 5. |
- Olsson, Bob, 1969, et al.
(author)
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Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura.
- 2005
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In: Thrombosis and haemostasis. - 0340-6245. ; 93:1, s. 139-44
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Journal article (peer-reviewed)abstract
- Idiopathic thrombocytopenic purpura (ITP) is an organ specific autoimmune disorder in which T-lymphocyte abnormalities have pathogenetic importance. In a DNA microarray screen of CD3+ T-lymphocytes from ITP patients and healthy controls we found an altered expression of genes associated with apoptosis, e.g. A20, caspase-8 and Bax. This together with our previous findings of increased gene expression of Fas, interferon-g and IL-2 receptor beta (IL2RB) indicated an altered activation induced cell death (AICD) of T-cells in ITP. Using a proliferation assay we found that CD3+ lymphocytes from ITP patients were significantly more resistant to dexamethasone induced suppression compared to normal lymphocytes. We also found that cultured CD3+ lymphocytes from ITP patients in remission were more susceptible to apoptosis both in the presence and absence of dexamethasone compared to cells from patient with active ITP and healthy controls, as indicated by increased staining of AnnexinV binding. Our findings suggest that apoptotic resistance of activated T-lymphocytes in patients with active ITP may lead to defective clearance of autoreactive T-lymphocytes through AICD, which might cause a continued immune destruction of platelets. Conversely, a loss of resistance to AICD in ITP patients in remission might be an important mechanism for the achievement of remission.
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| 6. |
- Schulman, S., et al.
(author)
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Ximelagatran for the secondary prevention of venous thromboembolism: a complementary follow-up analysis of the THRIVE III study
- 2005
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In: Thromb Haemost. - 0340-6245. ; 94:4, s. 820-4
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Journal article (peer-reviewed)abstract
- In the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13 patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and one VTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36; P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36; P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36, 1.93; P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.
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| 7. |
- Wolowacz, S. E., et al.
(author)
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Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis
- 2009
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In: Thrombosis and Haemostasis. - 0340-6245. ; 101:1, s. 77-85
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Journal article (peer-reviewed)abstract
- Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p > 0.15), or when all three trials were combined ( all p > 0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 - 1.10] and 1.05 [0.87 - 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.
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