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  • 1.
    Björkman, Sven
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Blanchette, V. S.
    Fischer, K.
    Oh, M.
    Spotts, G.
    Schroth, P.
    Fritsch, S.
    Patrone, L.
    Ewenstein, B. M.
    Collins, P. W.
    Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 4, p. 730-736Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient. OBJECTIVES: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing. PATIENTS: Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < or = 2 IU dL(-1)) in three clinical studies were included. RESULTS: In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment. CONCLUSION: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.

  • 2.
    Brekkan, Ari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berntorp, Erik
    Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
    Jensen, Kirsten
    Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
    Nielsen, Elisabet I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population Pharmacokinetics of Plasma-Derived Factor IX: Procedures for Dose Individualization2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 724-732Article in journal (Refereed)
    Abstract [en]

    Background: Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B. Objectives: The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization. Methods: The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL(-1). Results and conclusions: A three-compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg(-1) dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma-derived FIX products.

  • 3. Chaireti, R.
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bremme, K.
    Lindahl, T.
    Higher thrombin generation during the luteal phase of a normal menstrual cycle does not depend on inflammatory activity2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S2, p. 871-871Article in journal (Other academic)
  • 4. Chaireti, R.
    et al.
    Lindahl, T. L.
    Bremme, K.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Inflammatory and endothelial markers and their relations to the haemostatic potential during the menstrual cycle2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 614-614, article id PO292-TUEArticle in journal (Other academic)
  • 5.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL102008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, p. 986-994Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: P-selectin and CD40L expressed by activated platelets induce tissue factor (TF) and inflammatory cytokines in monocytes, but little is known of the cellular signaling pathways involved. The anti-inflammatory cytokine IL10 reduces atherosclerotic plaque formation. OBJECTIVES: To evaluate the importance of P-selectin upon platelet-monocyte aggregate (PMA) formation in thrombin receptor activator peptide (TRAP) stimulated whole blood, the P-selectin-P-selectin glycoprotein ligand (PSGL)-1-induced cellular signaling pathway, and the effects of IL10 on these functions. METHODS: TF, IL8, and monocyte chemotactic protein-1 (MCP-1) production, PMAs and phosphorylation of Lyn were analyzed in whole blood, purified monocytes, and vitamin D(3)-differentiated U-937 cells stimulated with TRAP or P-selectin with or without IL10. Anti-P-selectin or anti-CD40L antibodies (Abs), Src-kinases inhibitors, SU6656 or PP2, were added in some experiments. RESULTS: TRAP and P-selectin increased TF, IL8, and MCP-1 mRNA in whole blood and purified monocytes. Anti-P-selectin Ab reduced TRAP-induced PMA formation by 80 +/- 2% (P = 0.001) and production of TF (P = 0.04) and IL8 (P = 0.01). IL10 and SU6656 had no effect on PMA formation, although both significantly reduced TF (P = 0.002 and P = 0.02) and IL8 (P = 0.009 and P = 0.001) mRNA upon TRAP and P-selectin stimulation. Induced Lyn phosphorylation in monocytes was diminished by SU6656 (P = 0.02), anti-P-selectin Ab (P = 0.02), and IL10 (P = 0.03) upon TRAP or P-selectin stimulation. These results were confirmed in the vitamin D(3)-differentiated U-937 cells. CONCLUSIONS: The formation of PMAs in whole blood was P-selectin-dependent in the long term. P-selectin-PSGL-1-induced TF and IL8 expression through Lyn phosphorylation, and part of the inhibitory effect of IL10 depends on reduced phosphorylation.

  • 6.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jönelid, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    The change of the amount of circulating microparticles and their association to the general atherosclerotic burden after acute coronary syndrome2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 214-214, article id OR312Article in journal (Other academic)
  • 7.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bylock, A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Long-term treatment with ximelagatran, an oral direct thrombin inhibitor, persistently reduces the coagulation activity after a myocardial infarction2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 10, p. 2245-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In the ESTEEM study, patients with a recent myocardial infarction were treated with aspirin and randomized to one of four doses (24-60 mg b.i.d) of the oral direct thrombin inhibitor ximelagatran or placebo for 6 months. Ximelagatran and aspirin reduced the risk of recurrent ischemic events compared with aspirin alone. In the present substudy we evaluated the different doses of ximelagatran on pharmacokinetics as measured by plasma concentration of the active compound melagatran and activated partial thromboplastin time (APTT) and pharmacodynamics as related by markers for coagulation activity, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. METHODS AND RESULTS: Plasma samples from 518 patients were collected before, during and after the treatment period. There was a linear dose-concentration relation at peak and trough and a linear relation between concentration and APTT (P < 0.001). F1 + 2 and D-dimer were decreased by 25% and 52% at 1 week (P < 0.001) in the ximelagatran groups compared with the placebo group and the reductions were maintained during the 6 months treatment. There were no differences detected in F1 + 2 or D-dimer levels between the different ximelagatran dosages. There was no correlation between the melagatran concentration and the change in F1 + 2 and D-dimer levels. After cessation of ximelagatran F1 + 2 and D-dimer levels returned to the initial levels. CONCLUSION: The dose of ximelagatran and APTT are linearly related to the plasma concentration of melagatran. Ximelagatran induces a sustained and stable reduction of thrombin generation and fibrin turnover without any relation to dose above 24 mg b.i.d. These properties indicate that long-term treatment with a low dose of ximelagatran may provide valuable depression of coagulation activity in aspirin treated post myocardial infarction patients.

  • 8.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, J. H.
    Ansell, J.
    De Caterina, R.
    Gersh, B. J.
    Granger, C. B.
    Hanna, M.
    Horowitz, J. D.
    Huber, K.
    Husted, S.
    Hylek, E. M.
    Lopes, R. D.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    D-dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation: observations from the ARISTOTLE trial2014In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 12, no 9, p. 1401-1412Article in journal (Refereed)
    Abstract [en]

    BackgroundD-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. ObjectivesTo evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. MethodsIn the ARISTOTLE trial, 18201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14878 patients at randomization. The cohort was separated into two groups; not receiving vitaminK antagonist (VKA) treatment and receiving VKA treatment at randomization. ResultsHigher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR][Q4 vs. Q1]1.72, 95% confidence interval [CI]1.14-2.59, P=0.003), death (HR[Q4 vs. Q1]4.04, 95%CI3.06-5.33) and major bleeding (HR[Q4 vs. Q1]2.47, 95%CI1.77-3.45, P<0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS(2) score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level. ConclusionIn anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level.

  • 9. Collins, P. W.
    et al.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fischer, K.
    Blanchette, V.
    Oh, M.
    Schroth, P.
    Fritsch, S.
    Casey, K.
    Spotts, G.
    Ewenstein, B. M.
    Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 2, p. 269-275Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prophylactic factor (F)VIII has been shown to reduce bleeds and arthropathy in patients with severe hemophilia A. OBJECTIVES: Assuming that the trough FVIII level is an important determinant of the efficacy of prophylaxis, this paper addresses the effect of the inter-patient variability in pharmacokinetics and different dosing regimens on trough levels. METHODS: Simulations used FVIII half-lives and in vivo recoveries (IVR), observed during clinical trials with Advate [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method], and commonly used prophylactic regimens to calculate their effect on FVIII levels during prophylaxis. RESULTS AND CONCLUSIONS: Half-life and dose frequency had a larger effect on trough FVIII and time per week with FVIII<1 IU dL(-1) than IVR and infused dose per kg. The combined effect of these parameters resulted in substantial inter-patient variability in the amount of FVIII required to sustain a desired trough level. Prophylactic regimens based on Monday, Wednesday, Friday dosing were less cost effective in maintaining a desired trough level throughout the week. Dose escalation on Friday to cover the weekend would require potentially harmful doses of FVIII in many patients, especially in young children where more than 50% would require a Friday dose of over 100 IU kg(-1) and some would require more than 400 IU kg(-1). Knowledge of individual patients' half-lives and alteration of frequency of infusions may allow the more cost-effective use of FVIII and potentially expand access to prophylaxis to a greater number of patients, especially in regions where healthcare resources are scarce.

  • 10. Collins, P. W.
    et al.
    Blanchette, V. S.
    Fischer, K.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oh, M.
    Fritsch, S.
    Schroth, P.
    Spotts, G.
    Astermark, J.
    Ewenstein, B.
    Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A2009In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 7, no 3, p. 413-420Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of prophylactic factor VIII (FVIII) to decrease hemophilic bleeding and arthropathy is well established. The rationale for this strategy is to convert patients with severe hemophilia A to a moderate clinical phenotype by reducing time spent with a FVIII level <1 IU dL(-1). Studies to date, however, have not demonstrated a strong link between FVIII level and the bleeding rate. OBJECTIVES: To assess the effect of FVIII level on break-through bleeding in patients with severe hemophilia A on prophylaxis. PATIENTS/METHODS: This study analysed data from 44 patients aged 1-6 and 99 patients aged 10-65 years with severe hemophilia A (FVIII <1 IU dL(-1)) who were treated with prophylactic FVIII as part of clinical studies assessing pharmacokinetics, safety and efficacy of a recombinant FVIII (Advate). Each patient had pharmacokinetic measurements and FVIII infusions recorded, and these were used to calculate time spent with a FVIII below 1, 2 and 5 IU dL(-1). RESULTS: The data demonstrate that increasing time with a FVIII below 1 IU dL(-1) is associated with increased total bleeds and hemarthroses. Lack of adherence to the intended frequency of FVIII infusion was the most important determinant of low FVIII and increased bleeding. In children aged 1-6 years, the rate of bleeding was also influenced by FVIII half-life and clearance. Conclusions: These data have important implications for the management of patients with severe hemophilia.

  • 11. Dahl, O. E.
    et al.
    Quinlan, D. J.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Eikelboom, J. W.
    A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 9, p. 1966-1975Article in journal (Refereed)
    Abstract [en]

    Summary Background: Anticoagulants are effective for the prevention of venous thromboembolism (VTE) but cause bleeding. Interpretation of the risks and benefits of new anticoagulant regimens for VTE prevention is complicated by a lack of standardized definitions and reporting of bleeding. We reviewed the reporting of bleeding in randomized controlled trials of new anticoagulants compared with standard doses of enoxaparin in hip and knee arthroplasty, and examined the possible impact of differences in the definition of major bleeding on interpretation of the trial results. Methods: Electronic searches identified 16 phase III trials published between 2001 and 2010 involving 41,265 patients comparing one of 5 new anticoagulants with a common comparator, enoxaparin. Results: Major bleeding rates in patients treated with enoxaparin ranged from 0.1% to 3.1% in hip arthroplasty trials and from 0.2% to 1.4% in knee arthroplasty trials. In studies that excluded surgical-site bleeding from the definition, major bleeding rates were about 10-fold lower than in those which included surgical-site bleeding. Within the individual trials, the choice of bleeding definition and the methods of assessment of bleeding influenced the conclusions regarding the risk of bleeding with new anticoagulant regimens relative to enoxaparin. Eight of the 16 studies demonstrated a >/=40% relative risk differences in major bleeding between treatment groups but the difference was statistically significant in only two of these trials. Conclusion: Randomized VTE prevention trials report markedly different rates of major bleeding despite similar patient populations and doses and durations of anticoagulant prophylaxis and were underpowered to detect modest differences in patient-important bleeding events. Standardization of bleeding definitions and reporting seems desirable.

  • 12. Douketis, J.
    et al.
    Healey, J. S.
    Brueckmann, M.
    Fraessdorf, M.
    Spyropoulos, A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Oldgren, J.
    Reilly, P.
    Ezekowitz, M.
    Connolly, S.
    Yusuf, S.
    Bleeding and thromboembolic outcomes in warfarin-and dabigatran-treated patients in the RE-LY trial who required an urgent surgery or procedure2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 393-394, article id PO362-MONArticle in journal (Other academic)
  • 13.
    Edén, Desireé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Mokhtari, Dariush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue factor/factor VIIA signaling promotes cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 465-465, article id PO563-MONArticle in journal (Other academic)
  • 14. Eikelboom, J. W.
    et al.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Yusuf, S.
    Ezekowitz, M. D.
    Reilly, P. A.
    Brueckmann, M.
    Clemens, A.
    Connolly, S. J.
    Does dabigatran improve stroke-prevention in atrial fibrillation?: Reply to a rebuttal2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 6, p. 1438-1439Article in journal (Refereed)
  • 15.
    Ekstrand, C.
    et al.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Linder, M.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, H.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Bahmanyar, S.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Increased susceptibility to infections before the diagnosis of immune thrombocytopenia2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 807-814Article in journal (Refereed)
    Abstract [en]

    Background Infections after diagnosis of primary chronic immune thrombocytopenia (cITP) have mostly been connected to the immunomodulation treatment. Infections may trigger autoimmune diseases and may be a complication of an already impaired immune system. Objectives To investigate the association of cITP with infection before diagnosis. We also estimated the incidence of cITP based on the new definition by the International ITP Working Group. Methods We identified 1087 adults with primary cITP between 2006 and 2012 using the Swedish Patient Register. Data on infections not already associated with secondary ITP were also retrieved from the register. The standardized incidence ratios (SIRs), using the rates from the general population, and 95% confidence intervals (CIs) were estimated as a measure of relative risk. We used data from the Prescribed Drug Register to estimate SIR for anti-infective treatment. Results The incidence of cITP was 2.30 per 100 000 person-years (95% CI, 2.15-2.45). cITP was associated with an increased risk of serious infections requiring inpatient or outpatient care within 5 years before cITP diagnosis (SIR = 8.74; 95% CI, 7.47-10.18). Higher magnitude SIRs were observed for candidiasis, viral infection at an unspecified site and acute upper respiratory infections. For anti-infective drugs the SIR was 1.37 (1.25-1.50) and the highest SIRs were observed for amoxicillin, macrolides, nitrofurantoin and antivirals. Conclusion Patients with cITP have increased risks of infection and anti-infective treatments before their cITP diagnosis, with a more marked risk for candidiasis and viral infections. The findings indicate that infection is not only related to the immunomodulation treatment but also to the disease itself.

  • 16.
    Eliasson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Acosta, S.
    Sternby, N. H.
    Ögren, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23,796 consecutive autopsies2006In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 4, no 9, p. 1897-1902Article in journal (Refereed)
    Abstract [en]

    Background: The relationship between atherothrombotic disease and venous thromboembolism (VTE) remains unclear. Patients and methods: In a cohort of 23 796 consecutive autopsies, performed using a standardized procedure and representing 84% of all in-hospital deaths between 1970 and 1982 in an urban Swedish population, we investigated the relationship between verified arterial thrombosis and VTE, with the hypothesis that patients with thrombosis in major artery segments have increased odds of VTE. Results: We found an increased risk of VTE in patients with arterial thrombosis (Odds ratio; OR adjusted for gender and age 1.4, 95% confidence interval; CI 1.3-1.5) (P < 0.001). Patients with cervico-cranial and peripheral artery thrombosis had an excess risk even when controlling for age and major concomitant diseases. A negative association between coronary thrombosis and VTE in the univariate analysis (OR 0.7; 95% CI 0.6-0.8) (P < 0.001), was less pronounced in the multivariate analysis (OR 0.8; 95% CI 0.7-1.0) (P = 0.016). Conclusions: A positive association between atherothrombosis and VTE was confirmed, except in patients with coronary thrombosis, where IHD as competing death cause is a possible confounder. Our findings indicate a potential for directed prevention, but may also imply similarities in etiology.

  • 17.
    Eriksson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hedge, G.
    Navani, S.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Cross-talk between tissue factor and EPHA2 in cancer: potentiation of ligand-dependent EPHA2-signaling in vitro and co-expression in human colorectal cancer specimens2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 111-111, article id OR046Article in journal (Other academic)
  • 18. Francis, C. W.
    et al.
    Kessler, C. M.
    Goldhaber, S. Z.
    Kovacs, M. J.
    Monreal, M.
    Huisman, M. V.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Turpie, A. G.
    Ortel, T. L.
    Spyropoulos, A. C.
    Pabinger, I.
    Kakkar, A. K.
    Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12months: the DALTECAN Study2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no 6, p. 1028-1035Article in journal (Refereed)
    Abstract [en]

    BackgroundTreatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12months in cancer-associated VTE. MethodsPatients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12. FindingsOf 334 patients enrolled, 185 and 109 completed 6 and 12months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. ConclusionMajor bleeding was less frequent during dalteparin therapy beyond 6months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.

  • 19. Greinacher, A
    et al.
    Ittermann, T
    Bagemühl, J
    Althaus, K
    Fürll, B
    Selleng, S
    Lubenow, Norbert
    Department of Transfusion Medicine, Greifswald University, Germany.
    Schellong, S
    Sheppard, J I
    Warkentin, T E
    Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests.2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 9, p. 2025-31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is based on detection of heparin-dependent platelet-activating antibodies. Platelet factor 4 (PF4)/heparin enzyme-immunoassays (EIA) are a widely available surrogate for platelet-activating antibodies.

    OBJECTIVE: Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet-activating antibodies.

    PATIENTS/METHODS: Using quantile regression we determined the 97.5th percentile of PF4/heparin-immunoglobulin G (IgG) EIA reactivities in non-heparin-treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA-IgG reactivities (Greifswald laboratory; n = 2821) and the heparin-induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA-IgG (McMaster laboratory; n = 1956) with the serotonin-release assay (SRA).

    RESULTS: PF4/heparin-IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin-IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values.

    CONCLUSIONS: Results of PF4/heparin-IgG EIA should not be reported as only positive or negative as there is no single acceptable cut-off value. Instead, reporting PF4/heparin-IgG EIA OD results in ranges allows for risk-stratified prediction for presence of platelet-activating antibodies. Use of normalized OD ranges permits a standardized approach for inter-laboratory comparisons.

  • 20. Greinacher, A
    et al.
    Juhl, D
    Strobel, U
    Wessel, A
    Lubenow, Norbert
    Department of Transfusion Medicine, Greifswald University, Germany.
    Selleng, K
    Eichler, P
    Warkentin, T E
    Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes.2007In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 5, no 8, p. 1666-73Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Platelet-activating antiplatelet factor 4/heparin (anti-PF4/heparin) antibodies are the major cause of heparin-induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzyme-immunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved.

    METHODS: Consecutive patient sera (n = 1650) referred for diagnostic HIT testing were screened prospectively by both the heparin-induced platelet activation (HIPA) test and anti-PF4/heparin EIA - including individual classes (IgG, IgA, IgM) - with clinical correlations studied. Platelet microparticle and annexin-V-binding properties of the sera were also investigated.

    RESULTS: Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIA-positive, and, notably, only one serum was HIPA-positive/EIA-negative. Of 185 EIA-positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA-positive (1.117 vs. 0.768; P < 0.0001), with widely overlapping values. Two HIPA-positive but EIA-IgG-negative sera became HIPA-negative following IgG depletion, suggesting platelet-activating antibodies against non-PF4-dependent antigens. Clinical correlations showed that HIPA-negative/EIA-positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin-V binding.

    CONCLUSIONS: The anti-PF4/heparin EIA has high ( approximately 99%) sensitivity for HIT. However, only about half of EIA-positive patients are likely to have HIT. Anti-PF4/heparin antibodies of IgM/A class and non-PF4-dependent antigens have only a minor role in HIT.

  • 21.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, P. H.
    Andersson, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Magotti, P.
    Lambris, J. D.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Complement activation triggered by chondroitin sulfate released by thrombin receptor-activated platelets2008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 8, p. 1413-1421Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chondroitin sulfate (CS) is a glycosaminoglycan released by activated platelets. OBJECTIVE: Here we test the hypothesis that CS released by activated platelets can trigger complement activation in the fluid phase. METHODS AND RESULTS: Thrombin receptor-activating peptide (TRAP)-6 was used to activate platelets in platelet-rich plasma and blood, anticoagulated with the thrombin inhibitor lepirudin. TRAP activation induced fluid-phase complement activation, as reflected by the generation of C3a and sC5b-9, which could be attenuated by the C3 inhibitor compstatin. Chondroitinase ABC treatment of supernatants from activated platelets totally inhibited the activation, indicating that platelet-derived CS had initiated the complement activation. Furthermore, addition of purified CS to plasma strongly triggered complement activation. C1q was identified as the recognition molecule, as it bound directly to CS, and CS-triggered complement activation could be restored in C1q-depleted serum by adding purified C1q. TRAP activation of whole blood increased the expression of CD11b on leukocytes and generation of leukocyte-platelet complexes. It was demonstrated that these leukocyte functions were dependent on C3 activation and signaling via C5a, as this expression could be inhibited by compstatin and by a C5aR antagonist. CONCLUSIONS: We conclude that platelets trigger complement activation in the fluid phase by releasing CS, which leads to inflammatory signals mediated by C5a.

  • 22. Harenberg, Job
    et al.
    Kakkar, A.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Barrowcliffe, T.
    Casu, B.
    Fareed, J.
    Mismetti, P.
    Ofosu, F. A.
    Raake, W.
    Samama, M.
    Schulman, S.
    Recommendations on biosimilar low-molecular-weight heparins2009In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 7, no 7, p. 1222-1225Article in journal (Refereed)
    Abstract [en]

    Based on the results of large clinical trials, several low-molecular-weight heparins (LMWHs) have been approved for prophylaxis and the treatment of venous and arterial thromboembolism. As a result of expiration or pending expiration of patent protection of the originator LMWHs, many generic or biosimilar LMWHs have been approved in some countries and more are likely to be approved elsewhere. Their greater availability may reduce the treatment costs. The Working Party on Requirements for Development of Biosimilar LMWHs of the Subcommittee on Control of Anticoagulation, Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis has reached a consensus on recommendations to ensure the quality of biosimilar LMWHs as compared with the originator LMWHs.

  • 23. Hatch, E.
    et al.
    Wynne, H.
    Avery, P.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kamali, F.
    Application of a pharmacogenetic-based warfarin dosing algorithm derived from British patients to predict dose in Swedish patients2008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 6, p. 1038-1040Article in journal (Refereed)
  • 24. Iglesias, M. J.
    et al.
    Bruzelius, M.
    Hong, M-G
    Tregouet, D. A.
    Perisic, L.
    Franberg, M.
    Parini, P.
    Ganna, A.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Nilsson, P.
    Hedin, U.
    Uhlen, M.
    Silveira, A.
    Morange, P. E.
    Hamsten, A.
    Schwenk, J. M.
    Odeberg, J.
    An affinity proteomics study for plasma biomarker candidates of cardiovascular disease in venous thromboembolism2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 956-956, article id PO564-WEDArticle in journal (Other academic)
  • 25. Kakkar, A.
    et al.
    Kessler, C.
    Goldhaber, S. Z.
    Kovacs, M. J.
    Spyropoulos, A. C.
    Ortel, T. L.
    Pabinger, I
    Huisman, M. , V
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Monreal, M.
    Turpie, A. G.
    Francis, C. W.
    Dalteparin sodium for the long-term management of venous thromboembolism in cancer patients. The DALTECAN Study2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S2, p. 18-19Article in journal (Other academic)
  • 26.
    Kask, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Jorsback, A.
    Winkvist, M.
    Ek, B.
    Bergquist, J.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Proteomic analysis of tissue factor activation2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S2, p. 379-380Article in journal (Other academic)
  • 27.
    Kozarcanin, Huda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lood, Christian
    Munthe-Fog, Lea
    Sandholm, Kerstin
    Hamad, Osama A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bengtsson, Anders A
    Skjoedt, Mikke-Ole
    Huber-Lang, Markus
    Garred, Peter
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 3, p. 531-545Article in journal (Refereed)
    Abstract [en]

    Background: The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor invitro. In vivo studies also show that MASP-1 is involved in thrombogenesis.

    Objectives: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions.

    Methods: Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2.

    Results: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation.

    Conclusions: MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions invitro and invivo, and may represent a novel activation/amplification mechanism in thromboinflammation.

  • 28.
    Li, Xiujuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Embryonic stem cell models in vascular biology2009In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 7, no Suppl. 1, p. 53-56Article, review/survey (Refereed)
    Abstract [en]

    Embryonic stem cells have become an established tool in vascular biology to study the details of vasculogenesis as well as angiogenesis. There is also a future potential in using embryonic stem cell-derived endothelial cells for therapeutic purposes. It is important to evaluate this model by comparing features of endothelial cells derived from differentiating stem cells and their responsiveness to external stimuli to those of primary endothelial cells and to in vivo models. Through culture of mouse embryonic stem cell we discovered that differentiating stem cells are highly amenable to analyzing biochemical and cell biologic processes that are independent of flow. Endothelial cell function can be studied in the context of mutations or deletions that are embryonically lethal in vivo. Many, if not all, of the features of sprouting angiogenesis in differentiating stem cells closely mimic the in vivo process.

  • 29. Liesenfeld, K. -H
    et al.
    Lehr, T.
    Dansirikul, C.
    Reilly, P. A.
    Connolly, S. J.
    Ezekowitz, M. D.
    Yusuf, S.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Haertter, S.
    Staab, A.
    Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial: reply to a rebuttal2012In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 10, no 3, p. 502-504Article in journal (Refereed)
  • 30. Liesenfeld, K-H
    et al.
    Lehr, T.
    Dansirikul, C.
    Reilly, P. A.
    Connolly, S. J.
    Ezekowitz, M. D.
    Yusuf, S.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Haertter, S.
    Staab, A.
    Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial2011In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 9, no 11, p. 2168-2175Article in journal (Refereed)
    Abstract [en]

    Background: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. Objectives: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. Patients and methods: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. Results: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. Conclusions: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.

  • 31.
    Lubenow, Norbert
    et al.
    Department of Transfusion Medicine, Greifswald University, Germany.
    Eichler, P
    Lietz, T
    Greinacher, A
    Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3.2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 11, p. 2428-36Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To assess efficacy and safety of lepirudin in patients with heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as in a combined analysis of all HAT study data.

    PATIENTS/METHODS: Patients with laboratory-confirmed HIT were treated with lepirudin in three different aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints were new thromboembolic complications (TEC), limb amputations, and death and major bleeding. A historical control group (n = 120) was used for comparison.

    RESULTS: After start of lepirudin in 205 patients treated in HAT-3, the combined endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%) underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all prospective HAT trials (n = 403), after start of lepirudin treatment, the combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22 limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings. Compared with the historical control group (log-rank test), the combined endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473), primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008). Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P = 0.0148).

    CONCLUSIONS: The rate of new TECs in HIT patients is low after start of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by reducing the starting dose to 0.1 mg kg(-1) h(-1).

  • 32. Nasser, N J
    et al.
    Sarig, G
    Brenner, B
    Nevo, E
    Goldshmidt, O
    Zcharia, E
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vlodavsky, I
    Heparanase neutralizes the anticoagulation properties of heparin and low-molecular-weight heparin2006In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 4, no 3, p. 560-565Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Heparanase is a mammalian endo-D-glucuronidase that cleaves heparan sulfate (HS) in the extracellular matrix and cell surface. It is preferentially expressed by cells of the immune system and tumor cells. Heparanase overexpression in experimental tumor models results in increased angiogenesis and metastasis. Heparin and low-molecular weight heparin (LMWH) inhibit HS degradation by heparanase. OBJECTIVE: To investigate whether heparanase cleaves heparin and LMWH, and elucidate its effect on blood coagulation. METHODS: Heparin and LMWH were incubated with recombinant heparanase and subjected to measurements of molecular size (size exclusion chromatography) and anticoagulant activity (plasma APTT-activated thromboplastin time, and anti-Xa activity). APTT was also measured in plasma samples of transgenic mice overexpressing heparanase, in comparison with control mice. RESULTS: Incubation of heparin and LMWH with heparanase resulted in degradation of these substrates, as revealed by a significant decrease in their molecular weight. This was correlated with a marked suppression of the anticoagulant activity of heparin and LMWH, as indicated by a decreased effect on APTT and anti-Xa activity, respectively, when human plasma was added. Transgenic mice overexpressing heparanase exhibited a significantly shorter APTT than control mice. CONCLUSION: Heparanase is capable of degrading heparin and LMWH, so that its overexpression by tumor cells may contribute to heparin resistance, commonly occurring in cancer patients. In view of the complexity of the currently available heparanase activity assays, we propose an indirect approach to quantify heparanase activity by measuring the decrease in plasma APTT or anti-Xa activity exerted by the enzyme under the defined conditions.

  • 33.
    Razmara, M
    et al.
    Karolinska institutet.
    Hjemdahl, P
    Ostenson, C-G
    Li, N
    Platelet hyperprocoagulant activity in Type 2 diabetes mellitus: attenuation by glycoprotein IIb/IIIa inhibition.2008In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 12, p. 2186-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Platelets are hyperactive in Type 2 diabetes mellitus (T2DM), and antiplatelet treatment with glycoprotein (GP) IIb/IIIa inhibitors provides better thrombotic protection in DM than in non-diabetic subjects.

    OBJECTIVE: We hypothesized that diabetic platelets are hyperprocoagulant, and that this hyperactivity can be inhibited by GPIIb/IIIa blockade.

    METHODS: Patients with T2DM and gender/age/body mass index-matched non-diabetic controls were recruited (n = 12 for both) to study the effect of GPIIb/IIIa blockade on platelet procoagulant activity. Platelet phosphotidylserine (PS), factor (F) Va expression, and platelet-derived microparticle (PDMP) generation were measured by whole blood flow cytometry. Platelet-dependent thrombin generation and plasma clotting time were monitored in recalcified platelet-rich plasma.

    RESULTS: Compared to controls, basal platelet activation was similar, while thrombin receptor activating peptide stimulated activation was enhanced in patients with T2DM. Diabetic platelets also displayed more profound elevations of platelet PS exposure, FVa binding, and PDMP generation upon stimulation. These alterations resulted in a hyperprocoagulant state, as evidenced by a marked increase in the platelet procoagulant index, enhanced thrombin generation, and a shortened plasma clotting time. GPIIb/IIIa blockade by c7E3 or SR121566 decreased platelet PS exposure and FVa binding, and diminished platelet procoagulant activity in patients with T2DM.

    CONCLUSIONS: Platelets have increased procoagulant activity in patients with T2DM. The hyperprocoagulant activity is counteracted by GPIIb/IIIa blockade.

  • 34. Schenk, S
    et al.
    El-Banayosy, A
    Morshuis, M
    Arusoglu, L
    Eichler, P
    Lubenow, Norbert
    Department of Transfusion Medicine, Greifswald University, Germany.
    Tenderich, G
    Koerfer, R
    Greinacher, A
    Prohaska, W
    IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support.2007In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 5, no 2, p. 235-41Article in journal (Refereed)
    Abstract [en]

    Commercial immunoassays frequently detect anti-PF4/heparin antibodies during mechanical circulatory support (MCS), but only a small minority of patients develops heparin-induced thrombocytopenia (HIT). Whereas platelet functional tests can distinguish between platelet-activating and non-platelet-activating antibodies, commercial PF4-dependent immunoassays do not. Between 2003 and 2004, 113 patients were placed on MCS. Blood samples were obtained on postimplant day 5-7 for analyses by antibody assays and the functional heparin-induced platelet activation (HIPA) assay. Three distinct groups of patient sera were identified: platelet-activating anti-PF4/heparin antibodies (n = 10), non-platelet-activating anti-PF4/heparin antibodies (n = 53), and anti-PF4/heparin antibody negative (n = 50). Patients with platelet-activating antibodies had the highest risk for thromboembolic events (P < 0.005), whereas those with non-platelet-activating antibodies did not differ from antibody negative patients (P = 0.369). The enzyme-immunoassay and column agglutination assays, which cover all immunoglobulin classes, demonstrated adequate sensitivity and negative predictive value; yet, both lacked specificity with respect to the platelet-activating antibodies. If all antibody positive patients were further classified by an IgG-specific anti-PF4/heparin enzyme-immuno assay, specificity for platelet-activating antibodies increased. Whereas IgG-specific optical density (OD) values below 1.0 were likely for non-platelet-activating anti-PF4/heparin antibodies, higher values were progressively predictive for pathogenic platelet activation. The probability of the development of clinical HIT also increased steeply. In conclusion, platelet-activating anti-PF4/heparin antibodies are relatively common (about 9%) in patients on MCS and are associated with significantly higher thrombotic event rates. Low IgG-specific OD values (< 1.0) in the enzyme-immunoassay indicate low likelihood for the presence of platelet-activating antibodies. These results justify further validation so that anticoagulation during MCS becomes safer and adequate.

  • 35. Schulman, S.
    et al.
    Angerås, U.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Eriksson, B.
    Lassen, M. R.
    Fisher, W.
    Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 1, p. 202-204Article in journal (Refereed)
    Abstract [en]

    The definition of major bleeding varies between studies on surgical patients, particularly regarding the criteria for surgical wound-related bleeding. This diversity contributes to the difficulties in comparing data between trials. The Scientific and Standardization Committee (SSC), through its subcommittee on Control of Anticoagulation, of the International Society on Thrombosis and Haemostasis has previously published a recommendation for a harmonized definition of major bleeding in non-surgical studies. That definition has been adopted by the European Medicines Agency and is currently used in several non-surgical trials. A preliminary proposal for a parallel definition for surgical studies was presented at the 54(th) Annual Meeting of the SSC in Vienna, July 2008. Based on those discussions and further consultations with European and North American surgeons with experience from clinical trials a definition has been developed that should be applicable to all agents that interfere with hemostasis. The definition and the text that follows have been reviewed and approved by relevant co-chairs of the subcommittee and by the Executive Committee of the SSC. The intention is to seek approval of this definition from the regulatory authorities to enhance its incorporation into future clinical trial protocols.

  • 36. Schulman, S.
    et al.
    Angerås, U.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, B.
    Lassen, M. R.
    Fisher, W.
    Definition of major bleeding in surgery: an anesthesiologist's point of view: reply to a rebuttal2010In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 8, no 6, p. 1443-1444Article in journal (Refereed)
  • 37. Skagius, E
    et al.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Henriksson, A E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Fibrinolysis in patients with abdominal aortic aneurysm with special emphasis on rupture and shock2007In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 6, no 1, p. 147-150Article in journal (Refereed)
    Abstract [en]

    Background: A ruptured abdominal aortic aneurysm (AAA) is associated with high mortality. Postoperative complications such as hemorrhage, multiple organ failure, myocardial infarction, and thromboembolism are common. An active and balanced hemostatic system is essential to avoid bleeding as well as thrombosis. When these activities are not properly regulated the patient is at risk of developing either excessive bleeding or thrombosis-related complications. Previous studies have shown a state of activated coagulation in patients with ruptured AAA. However, there are conflicting results regarding the fibrinolytic response. Objectives: The aim of the present study was to investigate the fibrinolytic state pre-operatively in patients with ruptured and non-ruptured AAA in relation to the clinical outcome with special regard to the influence of shock. Methods: A prospective study was performed on 95 patients who underwent surgery for a ruptured AAA with shock (n = 43), a ruptured AAA without shock (n = 12), and a non-ruptured AAA (n = 40). Forty-one controls without an aneurysm were matched to the AAA patients according to age, gender and smoking habits. Plasma levels of tissue plasminogen activator antigen (tPAag), and plasminogen activator inhibitor type-1 (PAI-1) were measured as markers of fibrinolytic activity. D-dimer, a marker of fibrin turnover, was also measured. Results: D-dimer was significantly higher in patients with a non-ruptured AAA compared with controls without AAA. There were significantly higher levels of D-dimer, tPAag, and PAI-1 in patients operated for ruptured compared with non-ruptured AAA. tPAag was also significantly higher in ruptured AAA patients with shock compared with without shock. No deaths occurred in patients operated on for a non-ruptured AAA or ruptured AAA without shock. There were 12 deaths after repair of a ruptured AAA with shock, of which two patients died from bleeding and the remaining 10 from multiple organ failure and cardiac failure. Conclusion: Our results indicate a state of activated coagulation in patients with a non-ruptured AAA, the state being intensified by rupture. The present data show normal fibrinolytic activities in patients with a non-ruptured AAA, but increased systemic fibrinolysis, as demonstrated by elevated tPAag level, in patients with a ruptured AAA. The elevated PAI-1 level indicates a simultaneous inhibition of the systemic fibrinolysis. Furthermore, the hyperfibrinolytic state was reinforced by shock in this study. However, the clinical outcome, with a relatively high incidence of thrombosis-related deaths, indicate a prothrombotic state instead of a hyperfibrinolytic state as a major point of attention in patients with shock as a result of a ruptured AAA.

  • 38.
    Stage, Tore B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19, DK-5000 Odense, Denmark..
    Pottegard, A.
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19, DK-5000 Odense, Denmark..
    Henriksen, D. P.
    Odense Univ Hosp, Dept Clin Chem & Pharmacol, DK-5000 Odense, Denmark..
    Christensen, M. M. H.
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19, DK-5000 Odense, Denmark.;Odense Univ Hosp, Dept Clin Chem & Pharmacol, DK-5000 Odense, Denmark..
    Hojlund, K.
    Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense, Denmark..
    Brosen, K.
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19, DK-5000 Odense, Denmark..
    Damkier, P.
    Univ Southern Denmark, Dept Publ Hlth, Clin Pharmacol, JB Winslows Vej 19, DK-5000 Odense, Denmark.;Odense Univ Hosp, Dept Clin Chem & Pharmacol, DK-5000 Odense, Denmark..
    Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 1, p. 129-133Article in journal (Refereed)
    Abstract [en]

    Background: It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. Objectives: The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. Patients/methods: We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. Results: Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of -0.3 [95% CI: -0.1; -0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. Conclusion: Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.

  • 39.
    Thulin, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Yan, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    New technique to study cell-derived microparticles2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 627-627, article id PO330-TUEArticle in journal (Other academic)
  • 40. van Rooijen, Marianne
    et al.
    Hansson, L. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Frostegård, J.
    Silveira, A.
    Hamsten, A.
    Bremme, K.
    Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response2006In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 4, no 1, p. 77-82Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of inflammation in the pathogenesis of cardiovascular disease is well established. C-reactive protein (CRP) is the strongest independent predictor of myocardial infarction and stroke in women. Recent studies have indicated that CRP levels are raised during use of combined oral contraceptives (COCs). OBJECTIVES: The aim of the study was to investigate the effect of COCs on serum CRP levels and to indicate the underlying mechanisms of an expected increase. METHOD: In a prospective randomized cross over-study 35 women used two different preparations of COC, one second and one third generation. Serum levels of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), antibodies against oxidized LDL, insulin and insulin-like growth factor-I (IGF-I) along with insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 were analyzed before and during the two treatments. E-selectin, von Willebrand factor and factor VIII concentrations in plasma were also measured. RESULTS: A rise in serum CRP was observed during both treatments; the median level increased from 0.45 mg L(-1) at baseline to 1.48 mg L(-1) with second generation and to 2.02 mg L(-1) with third generation COC. The serum levels of SAA increased slightly during treatment with the third generation COC. IL-6 and TNFalpha were unaffected by treatment. Both preparations lowered IGF-I and raised IGFBP-1 and IGFBP-3 concentrations. CONCLUSION: The raised serum CRP concentration during treatment with COCs appears to be related to a direct effect on hepatocyte CRP synthesis and does not reflect IL-6 mediated inflammation, endothelial activation or induction of insulin resistance.

  • 41. Vilahur, Gemma
    et al.
    Hernández-Vera, Rodrigo
    Molins, Blanca
    Casaní, Laura
    Duran, Xevi
    Padró, Teresa
    Badimon, Lina
    Short-term myocardial ischemia induces cardiac modified C-reactive protein expression and proinflammatory gene (cyclo-oxygenase-2, monocyte chemoattractant protein-1, and tissue factor) upregulation in peripheral blood mononuclear cells2009In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 7, no 3, p. 485-493Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prompt coronary thrombus resolution, reducing time of ischemia, improves cardiac recovery. The factors triggered by ischemia that contribute to the clinical outcome are not fully known. We hypothesize that unabated inflammation due to cardiac ischemia may be a contributing factor.

    AIMS: As a proof-of-concept, we evaluated the effect of short-term myocardial ischemia on the local and systemic inflammatory response.

    METHODS: Pigs underwent either 90-min mid-left anterior descending (LAD) coronary artery balloon occlusion (infarct size 25% +/- 1% left ventricle; 29% heart function deterioration) or a sham-operation procedure. Peri-infarcted and non-ischemic cardiac tissue was obtained for histopathologic, molecular and immunohistochemical analysis of inflammatory markers [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), modified C-reactive protein (mCRP), and human alveolar macrophage-56 (HAM-56)]. Blood (femoral vein) was withdrawn prior to myocardial infarction (MI) induction (t = 0) and at 30 and 90 min to evaluate: (i) systemic cytokine levels (IL-6, TNF-alpha, CRP); (ii) proinflammatory gene and protein expression in peripheral blood mononuclear cells (PBMCs) of tissue factor (TF), cyclo-oxygenase-2 (Cox-2), monocyte chemoattractant protein-1 (MCP-1), and CRP; and (iii) platelet activation (assessed by perfusion studies and RhoA activation).

    RESULTS: Short-term ischemia triggered cardiac IL-6 and TNF-alpha expression, recruitment of inflammatory cells, and mCRP expression in infiltrated macrophages (P < 0.05 vs. t = 0 and sham). PBMC mRNA and protein expression of MCP-1, Cox-2 and TF was significantly increased by ischemia, whereas no differences were detected in CRP. Ischemia increased cardiac troponin-I, IL-6 and TNF-alpha systemic levels, and was associated with higher platelet deposition and RhoA activation (P < 0.001 vs. t = 0 and sham).

    CONCLUSION: Short-term myocardial ischemia, even without atherosclerosis, induces an inflammatory phenotype by inducing local recruitment of macrophages and systemic activation of mononuclear cells, and renders platelets more susceptible to activation.

  • 42. Westenbrink, B. D.
    et al.
    Alings, M.
    Connolly, S. J.
    Eikelboom, J.
    Ezekowitz, M. D.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Yang, S.
    Pongue, J.
    Yusuf, S.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    van Gilst, W. H.
    Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no 5, p. 699-707Article in journal (Refereed)
    Abstract [en]

    BackgroundAnemia may predispose to thromboembolic events or bleeding in anticoagulated patients with atrial fibrillation (AF). ObjectivesTo investigate whether anemia is associated with thromboembolic events and bleeding in patients with AF. Patients and methodsWe retrospectively analyzed the RE-LY trial database, which randomized 18113 patients with AF and a risk of stroke to receive dabigatran or warfarin for a median follow-up of 2years. Cox regression analysis was used to determine whether anemia predicted cardiovascular events and bleeding complications in these patients. ResultsAnemia was present in 12% of the population at baseline, and the presence of anemia was associated with a higher risk of thromboembolic cardiovascular events, including the composite endpoint of all-cause mortality or myocardial infarction (adjusted hazard ratio [HR]1.50, 95% confidence interval [CI]1.32-1.71) and the primary RE-LY outcome of stroke or systemic embolism (adjusted HR1.41, 95%CI1.12-1.78). Anemia was also associated with a higher risk of major bleeding complications (adjusted HR2.14, 95%CI1.87-2.46) and discontinuation of anticoagulants (adjusted HR1.40, 95%CI1.28-1.79). The association between anemia and outcome was similar irrespective of cardiovascular comorbidities, randomized treatment allocation, or prior use of warfarin. The incidence of events was lower in patients with transient anemia than in patients in whom anemia was sustained (adjusted HR0.66, 95%CI0.49-0.91). ConclusionsAnemia is associated with an increased risk of thromboembolic events, bleeding complications and mortality in anticoagulated patients with AF. These findings suggest that patients with anemia should be monitored closely during all types of anticoagulant treatment.

  • 43.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Eriksson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Mokhtari, Dariush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    The insulin-like growth factor 1 receptor mediates tissue factor/FVIIa-induced cell survival2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S2, p. 171-172Article in journal (Other academic)
  • 44.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue Factor non-coagulant signalling - molecular mechanisms and biological consequences with focus on cell migration and apoptosis2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no 5, p. 817-825Article in journal (Refereed)
    Abstract [en]

    Tissue factor (TF), a transmembrane glycoprotein, is the main initiator of the blood coagulation cascade. TF is also recognized as a true signalling receptor. There is accumulating evidence that the downstream signalling events by the TF-complexes are transduced by several mechanisms including; activation of the protease activated receptors (PAR)-1 and -2 and the PARs-dependent pathways, via the TF cytoplasmic domain and by transactivation of receptor tyrosine kinases. Triggering of signalling cascades such as the mitogen-activated protein kinase (MAPK) and PI3kinase/AKT pathways couples TF to a multitude of functions within the cell, such as proliferation, cell migration and survival. Thus, TF has a Janus face; on the one side vital life upholding functions and on the other harmful effects, exemplified in inflammation, the acute coronary syndromes and cancer. TF mediates a broad spectrum of signalling mechanisms. Learning more about these different mechanisms/pathways will lead to new treatment strategies, ultimately personalized.

  • 45.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tissue factor/FVIIA transactivates the IGF-1R in prostate cancer cells via inhibition of caveolin-12015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 707-707, article id PO552-TUEArticle in journal (Other academic)
  • 46.
    Åsberg, Signild
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Marie
    Umeå University, Department of Statistics.
    Henriksson, Karin M
    Lund University, Department of Laboratory Medicine.
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The Risk of Warfarin-Associated Hemorrhagic Stroke for the Years 2001 to 2009: An Analysis Based on 20 486 Stroke Patients in the Swedish Stroke Register2012In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836Article in journal (Refereed)
  • 47.
    Ögren, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Björck, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Acosta, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sternby, N H
    High incidence of concomitant venous thromboembolism in patients with portal vein thrombosis: a population study based on 23 796 consecutive autopsies2007In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 5, no 1, p. 198-200Article in journal (Refereed)
1 - 47 of 47
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