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  • 1.
    Alfredsson, Joakim
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Lindahl, Tomas L
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Gustafsson, Kerstin M
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Janzon, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Logander, Elisabeth
    Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: Results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, p. 335-340Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR.

    METHOD AND RESULTS: We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7-9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group.

    CONCLUSION: There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low.

  • 2.
    Chaireti, Roza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Jennersjö, Cecilia
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Is thrombin generation at the time of an acute thromboembolic episode a predictor of recurrence? The LInkoping Study on Thrombosis (LIST) - A 7-year follow-up2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, p. 135-139Article in journal (Refereed)
    Abstract [en]

    Introduction: Venous thromboembolism(VTE) is considered a chronic disease, since a high percentage of patients experience recurrences. Oral anticoagulants are effective in preventing recurrences at a price of potential bleeding complications, which underlines the importance of finding reliable markers for estimating the individual recurrence risk. In this report we evaluate thrombin generation markers at the time of an acute VTE as predictive markers for recurrence risk. Gender, presence of factor V Leiden and acquired provocative factors were taken into consideration. Additionally, we study the correlation between thrombin generation at the time of an acute VTE and thrombin generation measured four to eight weeks after discontinuation of anticoagulants. less thanbrgreater than less thanbrgreater thanMaterials and Methods: Themain cohort consisted of 115 patients with a confirmed thromboembolic event at inclusion. The follow-up period was seven years. less thanbrgreater than less thanbrgreater thanResults: Patients with an initial unprovoked VTE and at least one recurrence had significantly prolonged thrombin generation, whereas those without recurrences had higher maximum and total thrombin concentration. In contrast, when thrombin generation was measured one to two months after discontinuation of anticoagulant treatment, it was shown that the patients who experienced recurrences had higher maximum thrombin concentration. less thanbrgreater than less thanbrgreater thanConclusions: Our study shows that thrombin generation profiles at the time of a VTE correlate to the clinical course after the acute episode. The great over-lap in thrombin generation between patients with and without recurrences though, makes the use of thrombin generation profiles for advice on length of oral anticoagulation for an individual patient doubtful at the present stage of knowledge.

  • 3. Chaireti, Roza
    et al.
    Jennersjö, Cecilia
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lindahl, Tomas L
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Thrombin generation and D-dimer concentrations in a patient cohort investigated for venous thromboembolism. Relations to venous thrombosis, factor V Leiden and prothrombin G20210A. The LIST study.2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 2, p. 178-84Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The present study evaluated possible relations between various markers of thrombin generation, D-dimer and venous thromboembolism in outpatients with and without the FV Leiden and the protrombin mutations. PATIENTS AND METHODS: Our cohort consisted of 98 patients with the FV Leiden and 15 with the prothrombin mutation and an equal number of age- and gender-matched controls. All subjects were investigated due to suspicion of venous thromboembolism and the diagnosis was objectively confirmed or refuted. RESULTS: We compared the D-dimer values and the thrombin generation markers among different patient groups (with/without thromboembolism, with/without genetic factors, gender-linked). The only statistically significant difference noted was prolonged time both for the initiation and termination of thrombin generation in patients with thrombosis. This applied to controls and to patients heterozygous for the FV Leiden. Additionally, the D-dimer values were elevated in patients with the FV Leiden. No difference was found among the patients with prothrombin mutation and their controls. DISCUSSION: Multi-variant analysis indicated that the difference in D-dimer between FV Leiden patients and controls was due to the greater number of patients with confirmed thrombosis in the former group, a finding supported by an independent prospective study on postoperative thrombosis. Neither D-dimer concentration nor thrombin generation depend on FV Leiden. The total amount of thrombin generated was not related to diagnosis. The prolonged thrombin generation noted in controls and FV Leiden heterozygotes with thrombosis may point out different thrombin generation profiles in different patient populations and requires further studies.

  • 4.
    Chaireti, Roza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine. Karolinska Univ Hosp, Coagulat Unit, Div Haematol, Dept Med, Stockholm, Sweden.
    Rajani, Rupesh
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bergquist, Annika
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Melin, Tor
    Division of Gastroenterology & Hepatology, University Hospital, Lund, Sweden.
    Friis-Liby, Inga-Lill
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kapraali, Marjo
    Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Division of Medicine, Stockholm, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Almer, Sven
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Karolinska Inst, Dept Med, Solna, Sweden.
    Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 455-461Article in journal (Refereed)
    Abstract [en]

    Background: In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding.

    Aims: To evaluate the haemostatic potential in patients with liver disease.

    Methods: We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n=47), Budd-Chiari syndrome (BCS, n=15) and cirrhosis (n=24) and compared the results to those obtained from healthy controls (n=21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared with an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence]/[marker measured in the absence of thrombomodulin].

    Results: There were no differences between patients with BCS, patients on warfarin treatment and controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared with controls [p=0.006 for endogenous thrombin potential (ETP) and p<0.001 for peak thrombin. P<0.001 for both ratios ETP and peak] and patients with non-cirrhotic PVT (p=0.001, p=0.006, p<0.001, p<0.001 for ETP, peak, ratio ETP, ratio peak). The patients with cirrhotic PVT exhibited higher ETP (p=0.044) and peak (p=0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP ratio: p=0.001, peak ratio: p=0.001).

    Conclusions: Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer treatment with anticoagulants in this group.

  • 5.
    Holm, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Sederholm Lawesson, Sofia
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Zolfagharian, Shima
    Orebro Univ Hosp, Sweden.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Ekstedt, Mattias
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Alfredsson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Bleeding complications after myocardial infarction in a real world population - An observational retrospective study with a sex perspective2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 167, p. 156-163Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the current study was to assess bleeding events, including severity, localisation and prognostic impact, in a real world population of men and women with myocardial infarction (MI). Methods and results: In total 850 consecutive patients were included during 2010 and followed for one year. Bleeding complications were identified by searching of each patients medical records and characterised according to the TIMI criteria. For this analysis, only the first event was calculated. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all inhospital bleeding events was 13.2%, with no sex difference. Women had significantly more minor non-surgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women had also more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p=0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008). Conclusions: Almost one in four patients experienced a bleeding complication through 12 months follow-up after a myocardial infarction. Women experienced more non-surgery related minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome. In contrast men with non-surgery related bleeding complications had higher mortality. Improved bleeding prevention strategies are warranted for both men and women.

  • 6.
    Järemo, Petter
    et al.
    Department of Internal Medicine, Vrinnevisjukhuset, Norrköping, Sweden.
    Hansson, G.
    Department of Internal Medicine, Vrinnevisjukhuset, Norrköping, Sweden.
    Nilsson, O.
    Department of Internal Medicine, Vrinnevisjukhuset, Norrköping, Sweden.
    Elevated inflammatory parameters are associated with lower platelet density in acute myocardial infarctions with ST-elevation2000In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 100, no 6, p. 471-478Article in journal (Refereed)
    Abstract [en]

    Objective: Platelets and granulocytes play important roles in coronary disorders. We therefore, investigated platelet and granulocyte alterations in myocardial infarctions (MIs).

    Patients and study design: A total of 36 individuals having MI with raised ST-segments who were receiving thrombolytic therapy were studied. Sampling was carried out after thrombolysis within 24 h after hospital admission. After 3 to 6 months of recovery, 25 patients were reinvestigated. At the infarction, peak platelet density was determined using a special designed computerised apparatus. In addition, we did counts on platelets, neutrophils and monocytes. Moreover, plasma levels of soluble P-selectin, myeloperoxidase and interleukin 6 were determined to estimate the degree of platelet, neutrophil and monocyte activation, respectively. Peak platelet density was analysed at the MI. All other parameters were determined at the acute event and at recovery.

    Results: At the MI, compared to the recovery, platelet counts were lower (P<.001). In addition, increased neutrophil counts (P<.001), elevated monocyte counts (P<.001), enhanced myeloperoxidase (P<.001) and interleukin 6 (P<.001) levels were demonstrated. We failed to show elevated soluble P-selectin. Compared to individuals with ST-segment elevations and low platelet density (≤1.058 kg/l), patients having peak platelet densities >1.058 kg/l displayed lower neutrophil counts (P<.01) and decreased interleukin 6 levels (P<.01). Furthermore, we demonstrate that individuals with higher inflammatory response at the MI had higher neutrophil (r=.6; P<.01) and higher monocyte counts (r=.6; P<.001) at recovery.

    Conclusion: We conclude that MI is associated with an inflammatory response. However, a subgroup of patients having MI with ST-elevations and low peak platelet density was identified. Compared to subjects with higher platelet density, they had more severe inflammatory characteristics. The differences persisted during recovery.

  • 7.
    Järemo, Petter
    et al.
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Milovanovic, Micha
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Richter, Arina
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Letter: Elevated platelet density and enhanced platelet reactivity in stable angina pectoris complicated by diabetes mellitus type II2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 3, p. 373-374Article in journal (Other academic)
    Abstract [en]

    The prognosis of coronary heart disease (CHD) has changed for the better. Type II diabetes mellitus (T2DM) complicates CHD and is associated with less favorable prospects and higher rates of coronary recurrence.

    149 individuals below 75 years of age subject to elective coronary angiography to evaluate chest pain were consented. Patients were eligible if they did not have a history of rheumatic disease. 51 individuals treated medically for T2DM were compared with the remaining subjects (n = 98). Blood samples were obtained before elective coronary angiography.A special designed optical apparatus was used to analyze peak platelet density. Platelet bound fibrinogen after provocation reflecting the activation of the GPIIb-IIIa receptor i.e. platelet reactivity was determined with the use of a flow cytometer.

    T2DM is associated with augmented platelet density (p < 0.001).Diabetic platelets displayed enhanced reactivity when stimulating with higher concentrations ADP (8.5 μmol/l) (p < 0.01) and TRAP-6 (74 μmol/l) (p < 0.001).

    DTII patients with stable angina pectoris showed enhanced platelet density, augmented platelet reactivity and increased MPV. Platelets are more reactive in DTII. More aggressive platelets may offer a explanation as to why DTII has an impact upon the prognosis of CHD.

     

  • 8.
    Lindahl, Tomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Wallstedt, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Gustafsson, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Persson, Egon
    Novo Nordisk AS, Denmark.
    Hillarp, Andreas
    Halmstad County Hospital, Sweden.
    More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 135, no 3, p. 544-547Article in journal (Refereed)
    Abstract [en]

    The number of patients on antithrombotic treatment due to atrial fibrillation and venous thromboembolism is increasing fast due to an aging population. A growing proportion will be treated with novel oral anticoagulants, the first in clinical use was the direct oral thrombin inhibitor dabigatran (Pradaxa (R)). A small percentage of the patients on dabigatran will experience serious bleeding or be in need of urgent surgery. The aim of this study was to test the effects of different hemostatic agents in potentially reversing the anticoagulant effects in vitro in blood or platelet-rich plasma (PRP) spiked with dabigatran. Whole blood or PRP was spiked with the active substance dabigatran, 200 mu g/L. We measured clotting time being induced by 1.4 pmol/L tissue factor using the instrument ReoRox2 (TM) and initial clot growth velocity from a tissue factor covered surface using the instrument Thrombodynamics Analyzer T-2 (TM). Dabigatran prolonged clotting time 5-fold but reduced clot growth velocity only slightly. The reversing effects of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant activated factor VII (rFVIIa) were then tested. APCC (1.8 U/mL) reduced the prolonged clotting time by 1/3, rFVIIa (2 mu g/L) only slightly (n = 10-20). The reduction was not significant using Mann-Whitney test but significant using t-test with Bonferronis correction for multiple comparisons, whereas PCC (0.56 U/mL) had no effect on clotting time. APCC doubled initial clot growth velocity, although even more in the absence of dabigatran. In conclusion, APCC and rFVIIa, but not PCC, seem to reverse, at least partially, some effects of dabigatran on coagulation parameters. Systematic evaluation of case reports, registries and, ultimately, randomized clinical trials are needed to elucidate potential benefit for patients. (C) 2014 Elsevier Ltd. All rights reserved.

  • 9.
    Lindberg, Ulrika
    et al.
    Lund Univ, Sweden.
    Svensson, Lisbeth
    Lund Univ, Sweden.
    Hellmark, Thomas
    Lund Univ, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Shannon, Oonagh
    Lund Univ, Sweden.
    Increased platelet activation occurs in cystic fibrosis patients and correlates to clinical status2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 162, p. 32-37Article in journal (Refereed)
    Abstract [en]

    Cystic fibrosis (CF) is an inflammatory lung disease. Platelets have an emerging role in inflammation, however previous studies of platelet activation in CF have generated conflicting results. In this study, we determined platelet function in CF patients and correlated platelet activation to establish clinical and laboratory parameters. Twenty-two patients, aged 20.7 to 54.4 (mean 34.0, SD 9.45) years and with a mean FEV1% pred (forced expiratory volume in one second, % of predicted) of 72 (SD 21.4, range 32-110) were recruited. A combination of platelet assays was used: platelet aggregation, platelet activation and platelet-leukocyte complex formation. Platelets from CF patients exhibited significantly increased aggregation when stimulated ex-vivo, a tendency towards increased platelet upregulation of CD62P, but no increase of GPIIb/IIIa activation (PAC-1). Platelet-monocyte complex (PMC) formation was significantly increased in CF patients compared to controls, while platelet-neutrophil complex formation was not. In the CF group, platelet aggregation correlates with levels of anti-neutrophil cytoplasmic antibodies (ANCA) with specificity for bactericidal/permeability-increasing protein (BPI), BPI-ANCA (r = 0.56). The formation of PMCs correlates with lung function decline (1-FEV1%), CRP and BPI-ANCA (r = 0.61, 0.55, 0.5). We therefore confirm the presence of increased platelet activation in CF patients, and determine that further evaluation of platelet activation in relation to prognostic factors in CF is warranted.

  • 10.
    Magnusson, Maria
    et al.
    Karolinska University Hospital, Sweden .
    Sten-Linder, Margareta
    Karolinska University Hospital, Sweden .
    Bergquist, Annika
    Karolinska University Hospital, Sweden .
    Rajani, Rupesh
    Karolinska University Hospital, Sweden .
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Fischler, Bjorn
    Karolinska University Hospital, Sweden .
    Nemeth, Antal
    Karolinska University Hospital, Sweden .
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    The international normalized ratio according to Owren in liver disease: Interlaboratory assessment and determination of international sensitivity index2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 132, no 3, p. 346-351Article in journal (Refereed)
    Abstract [en]

    Introduction: The international normalized ratio (INR) is used to prioritize liver disease patients for transplantation. Previous studies have shown high interlaboratory variability in Quick-based INR determinations in samples of patients with liver disease. We assessed Owren-based INR reagents for analyzing INR in patients with liver disease. Further, we determined the difference between international sensitivity index (ISI) for patients on vitamin K antagonists (ISIVKA) and ISI for patients with liver disease (ISIliver). less thanbrgreater than less thanbrgreater thanPatients and Methods: Twenty patients with liver disease were included, 10 with INR 1.8-3.6 (group A1) and 10 with INR 1.2-1.5 (group C1). Plasma from these patients was analyzed for Owren-based INR in eight Swedish laboratories using either of following reagents: SPA+, Owrens PT or Nycotest PT. To determine ISI liver, the reference thromboplastin RBT/05 and additional 41 patients with liver disease and 20 normal controls were included. ISIVKA was determined according to the WHO procedure. The difference between the ISIVKA and ISIliver was calculated. less thanbrgreater than less thanbrgreater thanResults: The coefficients of variance for the Owren based INR methods were 6.2% in group A1, 3.9 % in group C1 and 5.3% for all patients. The difference between ISIVKA and ISIliver were -0.4%, -0.7% and -0.2% for SPA+, Owrens PT and Nycotest PT respectively. less thanbrgreater than less thanbrgreater thanConclusions: Interlaboratory variation in INR analyses according to Owren in patients with liver disease is low and the difference between ISIVKA and ISIliver is below 10% with this method. ISIVKA can therefore be used in the INR calibration, for the Owren reagents studied, when analyzing plasma from patients with liver disease.

  • 11.
    Milovanovic, Micha
    et al.
    Linköping University, Department of Social and Welfare Studies, Health, Activity, Care. Linköping University, Faculty of Health Sciences.
    Lysen, J.
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry.
    Richter, Arina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Cardiology . Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Järemo, Petter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Cardiology . Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland, Department of Internal Medicine VHN.
    Identification of low-density plate and elevated let populations with increased reactivity alpha-granule content2003In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 111, no 01-Feb, p. 75-80Article in journal (Refereed)
    Abstract [en]

    The present study examines biochemical and functional characteristics of platelet density subpopulations together with their ability to mobilise intracellular fibrinogen when activated. Platelets from three healthy volunteers were investigated. The total platelet population was separated according to density in a linear Percoll(TM) gradient in a plasma-free milieu containing EDTA that binds soluble Ca2+. Subsequently, platelets from each individual were divided according to density into 11 or 12 aliquots. In all fractions, we determined platelet count, intracellular P-selectin and the ADP-evoked platelet fibrinogen binding as a measure of platelet reactivity together with the platelet dense body content. The work demonstrates that platelets use stored intracellular fibrinogen when activated. It also shows that the platelet-fibrinogen binding can be initiated in a surrounding depleted of Ca2+ and fibrinogen. Moreover, the study demonstrates subpopulations of light platelets having increased reactivity and more alpha-granules but less dense bodies. The biological significance of the findings needs to be elucidated. (C) 2003 Elsevier Ltd. All rights reserved.

  • 12.
    Nylander, Martina
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Åklint, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Larsson, Anders
    Department of Medical Sciences, University Hospital, Uppsala, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets2012In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 129, no 4, p. E51-E58Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Arterial thrombi contain more platelets than venous thrombi and are more resistant to fibrinolysis. This resistance could partly be due to plasminogen activator inhibitor 1 (PAI-1) secreted by platelets. The aim of this study was to elucidate differences between thrombin receptors protease-activated receptor (PAR) 1 and 4 and platelet storage, secretion and synthesis of platelet PAI-1, as compared to other platelet α-granule proteins such as VEGF and endostatin.

    MATERIALS AND METHODS:

    Human isolated platelets were incubated with thrombin (0.5U/ml), PAR1-activating peptide (AP) (0.4-30μM) or PAR4-AP (1.5-300μM) for up to 24hours. ELISA, western blot and fluorescence microscopy were used to measure secretion, contents and localization of PAI-1, VEGF and endostatin.

    RESULTS:

    Our results show that PAI-1 and VEGF might be co-localized and that endostatin does not co-localize with either PAI-1 or VEGF. PAI-1 and VEGF show a similar secretion pattern, being more sensitive to low grade PAR1 activation, but secretion was also observed with higher concentrations of PAR4-APs. PAI-1 is secreted in an active form. PAI-1 mRNA was found in platelets, and elevated levels of PAI-1 were detected after 24hours incubation of platelets.

    CONCLUSIONS:

    PAI-1 and VEGF, but not endostatin, might be stored in the same α-granule in human platelets. PAI-1 and VEGF also show a similar secretion pattern, being more sensitive to PAR1 than to PAR4 activation, but the secretion is not exclusively selective. Our results also show that platelet PAI-1 is increased if incubated for 24hours, both with addition of PAR1-activating peptide and without activation, which could indicate de novo synthesis.

  • 13.
    Nylander, Sven
    et al.
    Preclinical R&D, Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, Sweden.
    Mattsson, Christer
    Preclinical R&D, Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, Sweden.
    Ramström, Sofia
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation2003In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 111, no 1-2, p. 65-73Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to test the relative importance of the two adenosine diphosphate (ADP) receptors P2Y1 and P2Y12 in thrombin-induced platelet activation using specific receptor antagonists. Blood from healthy volunteers was incubated with MRS2179, a reversible P2Y1 antagonist, or AR-C69931, a reversible P2Y12 antagonist prior to activation with different concentrations of ADP or thrombin. Platelet function in whole blood was assayed by flow cytometry using the antibody PAC-1 to estimate the expression of conformational active αIIbβ3, the fibrinogen receptor. Complete inhibition of P2Y12 or P2Y1 abolished the ADP response, but only inhibition of P2Y12 reduced the thrombin-induced response. The relative inhibition of the thrombin response by complete inhibition of P2Y12 was most pronounced at thrombin concentrations just enough for complete PAR1 cleavage, which is sufficient to release all ADP, giving 70–86% inhibition. Above this concentration, the relative importance of P2Y12 inhibition decreased due to activation of ADP independent pathways. This study supports P2Y12 as a drug target compared with P2Y1.

  • 14.
    Peng, Xiang
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Jinan University, Guangdong, China.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Kurz, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. University of Örebro, Sweden.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Introduction: Proteinase 3 (PR3) is released from neutrophil azurophilic granules and exerts complex effects on the inflammatory process. PR3 catalyzes the degradation of a number of macromolecules, but the consequences on blood cells are less well defined. In the present study, the effect of PR3 on human platelets was thoroughly investigated. Methods: The experiments were performed on washed platelets freshly isolated from blood donated by healthy human volunteers. Platelets shape change and aggregation was measured on a Chrono-Log aggregometer. The phosphorylated form of MYPT1 was visualized by immunostaining. Platelet activation was further evaluated by flow cytometry. Results: PR3 induced platelet shape change but not aggregation. Flow cytometry analysis showed that PR3 induced no P-selectin expression or binding of fibrinogen to the platelets, and it did not change the activation in response to PAR1- or PAR4-activating peptides or to thrombin. Furthermore, Fura-2 measurement and immuno-blotting analysis, respectively, revealed that PR3 stimulated small intracellular Ca2+ mobilization and Thr696-specific phosphorylation of the myosin phosphatase target subunit 1 (MYPT1). Separate treatment of platelets with the Rho/Rho kinase inhibitor Y-27632 and the intracellular Ca2+ chelator BAPTA/AM reduced the shape change induced by PR3 whereas concurrent treatment completely inhibited it. Conclusion: The data shows that the neutrophil protease PR3 is a direct modulator of human platelets and causes shape change through activation of the Rho/Rho kinase and Ca2+ signaling pathways. This finding highlights an additional mechanism in the complex interplay between neutrophils and platelets.

  • 15.
    Pfister, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Letter: The VKORC1 promoter is occupied by c-Myc transcription factor in HepG2 cells2010In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 126, no 2, p. E150-E151Article in journal (Other academic)
    Abstract [en]

    n/a

  • 16.
    Ramström, Sofia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Rånby, Mats
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Effects of inhibition of P2Y1 and P2Y12 on whole blood clotting, coagulum elasticity and fibrinolysis resistance studied with free oscillation rheometry2003In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 109, no 5-6, p. 315-322Article in journal (Refereed)
    Abstract [en]

    Introduction: In vivo, initial platelet activation is likely caused by platelet contacts with collagen in the subendothelium or from the small amounts of thrombin formed by the tissue factor/factor VIIa complex. Our aim was to study the coagulative role of ADP released by the platelets after activation with strong stimuli such as collagen and/or thrombin, and the relative importance of the platelet ADP receptors P2Y1 and P2Y12.

    Materials and methods: We used 10 Hz free oscillation rheometry to measure clotting time, clot elasticity and fibrinolysis resistance of non-anticoagulated whole blood. The platelets were activated with a collagen-related peptide (CRP), with the PAR1 thrombin receptor activating peptide TRAP-6 or by thrombin, the latter generated by small amounts of thromboplastin. To inhibit the platelet ADP receptors, we used the P2Y1 antagonist MRS2179 and the P2Y12 antagonist AR-C69931MX.

    Results: Both antagonists significantly retarded the clotting induced by CRP. The effects were most pronounced with AR-C69931MX. For TRAP-6, the same trend was seen, but the retardation was only significant with AR-C69931MX. Clotting induced by small amounts of thromboplastin was not affected by any ADP-receptor antagonist. Addition of both antagonists did not change the results as compared to samples with AR-C69931MX alone. Nor did the antagonists, one at a time or in concert, effect fibrinolysis or the elastic properties of the clot.

    Conclusion: We conclude that ADP-receptor inhibition prolongs the clotting time for whole blood activated by CRP, but that it does not affect the properties of the subsequently formed coagulum.

  • 17.
    Ramström, Sofia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Rånby, Mats
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    The role of platelets in blood coagulation: effects of platelet agonists and GPIIb/IIIa inhibitors studied by free oscillation rheometry2002In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 105, no 2, p. 165-172Article in journal (Refereed)
    Abstract [en]

    We have studied the contribution of platelets to the coagulation of plasma and the effects of activation or inhibition of platelets on the coagulation process in unanticoagulated fresh whole blood (subsequently termed native blood). For this purpose, we have used a free oscillation rheometer (FOR), the ReoRox4, a new instrument that enables noninvasive viscoelastic measurements of clot formation in plasma and whole blood. Platelets appear essential for the initiation of coagulation if no activating surface is present. We prepared platelet-free plasma by quick centrifugation and filtration of native blood, which did not coagulate if stored in plastic containers at 37 °C but clotted if transferred to glass containers. Addition of platelet agonists, such as collagen or the thrombin receptor agonist peptide, SFLLRN, significantly accelerated the clotting of native blood and also changed the rheometer curve appearance, accelerating both onset and completion of clot formation (i.e. fibrin gel formation). Inhibition of platelet glycoprotein (GP) IIb/IIIa with the peptide-derived compound MK-852 or the antibody-derived abciximab (Reopro) prevented clot retraction and prolonged the clotting time with SFLLRN. In collagen-stimulated samples, MK-852 accelerated clotting but delayed completion of clotting while abciximab prolonged both clotting time and completion of clotting. To our knowledge, this is the first report showing that activation of platelets in native whole blood shortens the coagulation time ex vivo. It also describes a new instrument that enables studies of the viscoelastic properties of a forming whole blood clot.

  • 18.
    Ramström, Sofia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Vretenbrant-Öberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Åkerström, Finn
    Leicester Medical School University of Leicester, UK.
    Enström, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Platelet PAR1 receptor density-Correlation to platelet activation response and changes in exposure after platelet activation2008In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 121, no 5, p. 681-688Article in journal (Refereed)
    Abstract [en]

    Introduction: A polymorphism (-14 A/T) affecting PAR1 expression on the platelet surface has recently been identified. A two-fold variation in receptor density, which correlated with the platelet response to PAR1-activating peptide (PAR1-AP), has been reported. Materials and methods: We used flow cytometry to measure the correlation between the number of PAR1 receptors and platelet activation. We also measured the changes in receptor exposure after platelet activation with PAR1-AP, ADP, PAR4-AP or a collagen-related peptide (CRP). Results: In our study, the PAR1 receptor number varied almost four-fold, from 547 to 2063 copies/platelet (mean ± S.D. 1276 ± 320, n = 70). The number of PAR1 receptors on resting platelets correlated to platelet fibrinogen binding and P-selectin expression following platelet activation with PAR1-AP (r2 = 0.30, p < 0.01 and r2 = 0.15, p < 0.05, respectively, n = 36). The correlation was not improved by exclusion of the ADP-component from the PAR1-AP-induced response. We found a trend, but no statistically significant differences in PAR1 receptor number and platelet reactivity between A/A individuals and T/A or T/T individuals. Ex vivo activation with PAR1-AP decreased PAR1 surface exposure to 71 ± 19% of the exposure on resting platelets (mean ± S.D., p < 0.01, n = 19), while activation by ADP, PAR4-AP or CRP significantly increased the exposure, to 151 ± 27%, 120 ± 21% and 138 ± 25%, respectively (n = 11, 11 and 10). Conclusions: This study shows a large variation in PAR1 receptor number in healthy individuals, a variation correlated to the platelet activation response. We found a significant reduction in PAR1 surface exposure after adding PAR1-AP, while activation with ADP, PAR4-AP or CRP increased the exposure.

  • 19.
    Sanchez Centellas, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Gudlur, Sushanth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Nanyang Technology University, Singapore.
    Vicente Carrillo, Alejandro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    A cluster of aspartic residues in the extracellular loop II of PAR 4 is important for thrombin interaction and activation of platelets2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 154, p. 98-106Article in journal (Refereed)
    Abstract [en]

    Thrombin activates platelets via proteolytic cleavage of protease-activated receptors (PARs) 1 and 4. The two PARs have distinct but complementary roles. The mechanisms responsible for PAR1 activation by thrombin have been extensively studied. However, much less is known regarding thrombin activation of PAR4, especially the potential involvement of regions of PAR4 other than the N-terminal, which is bound to the catalytic site of thrombin. We have studied PAR4 in S. cerevisiae strainMMY12, an expression system in which the GPCR receptors are connected to a Lac Z reporter gene resulting in increased beta-galactosidase activity. This approach was used to assess PAR4 mutants to evaluate the contribution of different aspartic residues in facilitating PAR4 activation. Furthermore, peptides mimicking parts of the PAR4 N-terminal and the second extracellular loop (ECLII) were tested for their ability to inhibit platelet activation by thrombin. Binding of these peptides to gamma-thrombin was studied by monitoring the decrease in tryptophan fluorescence intensity of thrombin. We conclude that not only the N-terminal but also the electronegative aspartic residues D224, D230 and D235 (located in ECLII) are be important for PAR4 binding to thrombin. We further suggest that they play a role for the tethered ligand binding to the receptor, as mutations also affected activation in response to a PAR4-activating peptide mimicking the new N-terminal formed after cleavage. This agrees with previous results on PAR1 and thrombin binding. We suggest that the ECLII of PAR4 could be a potential target for antithrombotic drug development. (C) 2017 Elsevier Ltd. All rights reserved.

  • 20.
    Schonning, A.
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Karlen, J.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Frisk, T.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Heyman, M.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Svahn, J. E.
    Lund University, Sweden.
    Ora, I.
    Lund University, Sweden.
    Kawan, L.
    Sahlgrens University Hospital, Sweden.
    Holmqvist Persson, Britt-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Björklund, C.
    Umeå University Hospital, Sweden.
    Harila-Saari, A.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Ranta, S.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 152, p. 64-68Article in journal (Refereed)
    Abstract [en]

    Introduction: Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. Materials and ethods: We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18 years diagnosed with HL between January 2005 and December 2015 in Sweden. Results: Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4 years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17 years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. Conclusions: VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis. (C) 2017 Elsevier Ltd. All rights reserved.

  • 21.
    Sven, Nylander
    et al.
    Department of Molecular Pharmacology, Preclinical R and D, AstraZeneca R and D, Mölndal, Sweden.
    Mattsson, Christer
    Department of Molecular Pharmacology, Preclinical R and D, AstraZeneca R and D, Mölndal, Sweden.
    Lindahl, Tomas
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Characterisation of species differences in the platelet ADP and thrombin response2006In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 117, no 5, p. 543-549Article in journal (Refereed)
    Abstract [en]

    Introduction:

    A number of animal models are used to study platelet-dependent diseases. In the present investigation, we have used a simple flow cytometry assay to evaluate platelet function in man, rat, mouse, guinea pig and dog.

    Materials and methods:

    Platelet activation was evaluated in diluted whole blood by measuring fibrinogen binding to activated platelets using a polyclonal anti-human fibrinogen antibody that cross-reacts with fibrinogen from all species tested. The assay was used to evaluate platelet function with respect to ADP and thrombin sensitivity. The relative importance of the two platelet ADP receptors and total ADP in the thrombin response was also studied by using receptor-specific antagonists and apyrase, respectively.

    Results:

    Mouse platelets were most sensitive to both agonists. Unlike in man and dog the maximal response to ADP was greater than to thrombin in mouse, rat and guinea pig. P2Y12 blockade was in all species equally effective as ADP removal in inhibiting thrombin-induced platelet activation whereas P2Y1 blockade was almost ineffective.

    Conclusion:

    The present study describes a simple platelet function test that can be used to evaluate platelet function in man, rat, mouse, guinea pig and dog. Platelets from the tested species differed in their sensitivity to ADP and thrombin. In contrast to human and canine platelets, mouse, rat and guinea pig platelets displayed a stronger maximal response to ADP than to thrombin. In terms of the relative contribution of P2Y1 and P2Y12 in the thrombin response, the P2Y12 receptor was the key receptor in all species and its blockade gave equal effect as total removal of ADP.

  • 22.
    Venetsanos, Dimitrios
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Sederholm Lawesson, Sofia
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Gustafsson, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Wallen, Hakan
    Karolinska Institute, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.
    Erlinge, David
    Department of Cardiology, Clinical Sciences, Lund University, Skåne University Hospital, Lund, Sweden.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Alfredsson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 171, p. 38-44Article in journal (Refereed)
    Abstract [en]

    Background

    It remains unknown if bivalirudin compared to heparin confers any additional inhibition of platelet and coagulation activation during primary percutaneous coronary intervention(PPCI) after pretreatment with ticagrelor.

    Methods

    In this substudy of VALIDATE-SWEDEHEART trial, 103 patients pretreated with ticagrelor were randomized before PPCI to heparin or bivalirudin. Blood samples were collected before and 1 and 12 h after PPCI. We measured platelet reactivity (PR) using Multiplate, soluble P-selectin, thrombin-antithrombin complexes (TAT) and prothrombin fragments 1 + 2 (F1 + 2) as markers of platelet and coagulation activation.

    Results

    The median (IQR) time from ticagrelor administration to randomization was 63 (29) vs 60 (24) minutes, p = 0.28. ADP-induced PR did not significantly differ between groups over time (heparin vs bivalirudin, AUC 73 (62) vs 74 (68), p = 0.74, 32 (42) vs 43 (51), p = 0.38, 15 (15) vs 19 (15), p = 0.29, before, 1 and 12 h after PPCI). Soluble P-selectin did not significantly differ between groups. At 1 h TAT significantly increased with bivalirudin (3.0 (1.3) to 4.3 (4.2) ug/L; p < 0.01), but not with UFH (3.1 (2.1) to 3.5 (1.6) ug/L, p = 0.24). F1 + 2 increased in both groups but the rise was numerically higher with bivalirudin (170 (85) to 213 (126) pmol/L vs 168 (118) to 191 (103) pmol/L). At 12 h, a comparable significant increase in thrombin generation was observed in both groups.

    Conclusion

    In patients treated with ticagrelor, we found no major differences between bivalirudin and heparin in platelet aggregation or coagulation markers, which is in agreement with the neutral clinical results of the VALIDATE-SWEDEHEART study.

  • 23.
    Venetsanos, Dimitrios
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Sederholm Lawesson, Sofia
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Swahn, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Alfredsson, Joakim
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial.2017In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 149, p. 88-94Article in journal (Refereed)
    Abstract [en]

    AIMS: To provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets.

    METHODS: Ninety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU).

    RESULTS: There was no significant difference in PRU values at baseline. PRU 20min after LD were 237 (182-295), 112 (53-238) and 84 (29-129) and 60min after LD, 56 (15-150), 51 (18-85) and 9 (7-34) in integral, crushed and chewed ticagrelor LD, respectively (p<0.01 for both). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60min. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20min whereas no difference was observed at 60min. At 20min, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01).

    CONCLUSION: With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared to standard integral tablets. We also show that administration of chewed tablets is feasible and provides faster inhibition than either crushed or integral tablets.

    CLINICAL TRIAL REGISTRATION: European Clinical Trial Database (EudraCT number 2014-002227-96).

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