| 1. |
- Glise, Lars, 1988, et al.
(författare)
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Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo
- 2019
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:2, s. 223-233
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.
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| 2. |
- Johansson, Magdalena, et al.
(författare)
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Alcohol Consumption and Risk of First-Time Venous Thromboembolism in Men and Women
- 2019
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:6, s. 962-970
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The relationship between alcohol intake and risk of venous thromboembolism (VTE) is unclear. Men and women differ in their drinking habits, which may affect a possible association.OBJECTIVE: This article investigates the association between alcohol consumption, alcohol dependence and VTE in the total population as well as in men and women separately.METHODS: We performed a prospective, population-based cohort study in northern Sweden. Study participants were 108,025 (51% women) persons aged 30 to 60 years who underwent a health examination between 1985 and 2014. We assessed alcohol consumption and defined alcohol dependence using a questionnaire. The outcome was a validated first-time VTE.RESULTS: The mean follow-up time was 13.9 years, and 2,054 participants had a first-time VTE. The mean alcohol consumption was 3.5 standard drinks weekly in men and 1.5 in women. Alcohol dependence was found in 10% of men and 3% of women. There was an association between alcohol consumption (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.03 per standard drink weekly) as well as alcohol dependence (HR, 1.27; 95% CI, 1.06-1.52) and VTE after adjustments. In men, the risk of VTE increased over quartiles of weekly alcohol consumption (p for trend 0.02), with a HR of 1.22 (95% CI, 1.01-1.47) for the highest quartile. Alcohol dependence was associated with VTE in men (HR, 1.30; 95% CI, 1.07-1.59). In women, there were no significant associations.CONCLUSION: High alcohol consumption and alcohol dependence were associated with increased risk of first-time VTE in men, but not in women.
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| 3. |
- Judge, Heather M, et al.
(författare)
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Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function.
- 2010
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 103:6
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Tidskriftsartikel (refereegranskat)abstract
- The thienopyridine P2Y12 receptor antagonists clopidogrel and prasugrel prevent arterial thrombosis and are routinely used following percutaneous coronary intervention. However, the optimal level of P2Y12 blockade to effectively inhibit platelet function is unknown. These studies utilised the active metabolite of prasugrel (R-138727) to achieve a range of P2Y12 blockade in vitro and assessed several aspects of platelet function. Blood from healthy volunteers was incubated with R-138727 (0-10 microM). P2Y12 receptor number was assessed using a 33P-2MeSADP binding assay. Platelet aggregation (PA) was measured by optical aggregometry with ADP 2-20 microM. VASP phosphorylation, annexin V binding, microparticle formation and P-selectin expression were assessed by flow cytometry. Increasing numbers of unblocked receptors were required for a sustained aggregation response with decreasing concentrations of ADP. A P2Y12 receptor blockade of 60-80% resulted in strong inhibition of final PA response, P-selectin expression, microparticle formation and vasodilator-stimulated phosphoprotein (VASP). PA induced by ADP 2 microM and P-selectin expression were particularly sensitive to low levels of receptor blockade whereas the VASP phosphorylation assay was relatively insensitive, requiring 60% receptor blockade to achieve substantial inhibition. Different assays varied in their ability to discriminate particular ranges of P2Y12 blockade and 80% or greater P2Y12 receptor blockade is required for consistently strong inhibition of several aspects of platelet function. These data guide the interpretation of results from different assays used to monitor the effects of P2Y12 receptor antagonists.
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| 4. |
- Li, Jinan, et al.
(författare)
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Plasmin/plasminogen is essential for the healing of tympanic membrane perforations.
- 2006
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 96:4, s. 512-519
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen has been proposed to play an important role in different tissue remodeling processes such as wound healing and tissue regeneration after injuries. The healing of tympanic membrane perforations is a well-organized chain of inflammatory events, with an initial invasion of inflammatory cells followed by reparative and restoration phases. Here we show that the healing of tympanic membrane perforations is completely arrested in plasminogen-deficient mice, with no signs of any healing even 143 days after perforation. Inflammatory cells were recruited to the wounded area, but there were no signs of tissue debridement. In addition, removal of fibrin, keratinocyte migration and in-growth of connective tissue were impaired. This contrasts with skin wound healing, where studies have shown that, although the healing process is delayed, it reaches completion in all plasminogen-deficient mice. Our finding that keratinocyte migration and re-epithelialization were completely arrested in plasminogen-deficient mice indicates that plasminogen/plasmin plays a more profound role in the healing of tympanic membrane perforations than in the healing of other epithelial wounds.
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| 5. |
- Majeed, Ammar, et al.
(författare)
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Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding
- 2017
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Ingår i: Thrombosis and Haemostasis. - : MEDIZIN NATURWISSENSCHAFTEN. - 0340-6245 .- 2567-689X. ; 117:3, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- The optimal timing of vitamin K antagonists (VKAs) resumption after an upper gastrointestinal (GI) bleeding, in patients with continued indication for oral anticoagulation, is uncertain. We included consecutive cases of VKA-associated upper GI bleeding from three hospitals retrospectively. Data on the bleeding location, timing of VKA resumption, recurrent GI bleeding and thromboembolic events were collected. A model was constructed to evaluate the 'total risk', based on the sum of the cumulative rates of recurrent GI bleeding and thromboembolic events, depending on the timing of VKA resumption. A total of 121 (58%) of 207 patients with VKA-associated upper GI bleeding were restarted on anticoagulation after a median (interquartile range) of one (0.2-3.4) week after the index bleeding. Restarting VKAs was associated with a reduced risk of thromboembolism (HR 0.19; 95 % CI, 0.07-0.55) and death (HR 0.61; 95% CI, 0.39-0.94), but with an increased risk of recurrent GI bleeding (HR 2.5; 95% CI, 1.4-4.5). The composite risk obtained from the combined statistical model of recurrent GI bleeding, and thromboembolism decreased if VKAs were resumed after three weeks and reached a nadir at six weeks after the index GI bleeding. On this background we will discuss how the disutility of the outcomes may influence the decision regarding timing of resumption. In conclusion, the optimal timing of VKA resumption after VKA-associated upper GI bleeding appears to be between 3-6 weeks after the index bleeding event but has to take into account the degree of thromboembolic risk, patient values and preferences.
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| 6. |
- Osterlund, Barbro, et al.
(författare)
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Intracoronary beta2 receptor activation induces dynamic local t-PA release in the pig.
- 2003
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Ingår i: Thrombosis and haemostasis. - 0340-6245 .- 2567-689X. ; 90:5, s. 796-802
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Tidskriftsartikel (refereegranskat)abstract
- To investigate beta2 -adrenergic agonist-mediated effects on coronary fluxes of local fibrinolytic factors, healthy anaesthetised and instrumented pigs (n=10) were studied during infusion of isoprenaline (IPR) into the left main coronary artery. Coronary net fluxes of total t-PA antigen, active t-PA and total PAI-1 antigen were determined at baseline and at 3, 5, 7 and 10 minutes of IPR infusion. During IPR, net release of total t-PA increased in a biphasic pattern with transiently high levels at 3 (+440 %) and 7 minutes (+620%) and returned towards baseline at 10 minutes. Net coronary release of active t-PA increased with maximum levels at 3 minutes (+50%). Baseline coronary net flux of total PAI -1 showed a decrease which was most pronounced at 10 minutes. To conclude, a fast beta2 agonist-mediated local release of t-PA into the coronary vasculature was demonstrated. For total t-PA, this response was characterised by a biphasic release profile.
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| 7. |
- Robb, A O, et al.
(författare)
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The influence of the menstrual cycle, normal pregnancy and pre-eclampsia on platelet activation
- 2010
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 103:2, s. 372-378
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Tidskriftsartikel (refereegranskat)abstract
- Platelet activation has a key role in mediating thrombotic and inflammatory events. This study aimed to determine the influence of the menstrual cycle, pregnancy and pre-eclampsia on in vivo platelet activation. Twelve healthy nulliparous, non-smoking women with regular menses were studied over a single menstrual cycle. Twenty-one healthy primigravida pregnant women were studied longitudinally at 16, 24, 32 and 37 weeks gestation and seven weeks post-partum. Sixteen primigravida women with pre-eclampsia were studied at time of diagnosis and at seven weeks post-partum. Platelet-monocyte aggregates and platelet-surface P-selectin expression were assessed by flow-cytometry. Soluble P-selectin and CD40 ligand (CD40L) were measured by ELISA. Markers of platelet activation did not vary over the menstrual cycle. Platelet-monocyte aggregates were greater in the third trimester of pregnancy compared to non-pregnant women (p=0.003). Platelet surface and plasma soluble P-selectin concentrations increased with gestation (p<0.0001) and were raised by 24 weeks of pregnancy compared to non-pregnant women (p< or =0.02 for both) and together with platelet monocyte aggregates, decreased post-partum (p< or =0.02). Soluble CD40L concentrations fell in pregnancy, reaching a nadir at mid-gestation (p=0.002). There were no differences in markers of platelet activation between normal and pre-eclamptic pregnancies. In conclusion, platelet activation is increased in pregnancy and increases with gestation but is unaffected by pre-eclampsia. This suggests that systemic platelet activation is a feature of pregnancy but this is not affected by established pre-eclampsia.
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| 8. |
- Sandén, Per, et al.
(författare)
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Bleeding complications and mortality in warfarin-treated VTE patients, dependence of INR variability and iTTR
- 2017
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 117:1, s. 27-32
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Tidskriftsartikel (refereegranskat)abstract
- High quality of warfarin treatment is important to prevent recurrence of venous thromboembolism (VTE) without bleeding complications. The aim of this study was to examine the effect of individual time in therapeutic range (iTTR) and International Normalised Ratio (INR) variability on bleeding risk and mortality in a large cohort of well-managed patients with warfarin due to VTE. A cohort of 16612 patients corresponding to 19502 treatment periods with warfarin due to VTE between January 1, 2006 and December 31, 2011 was retrieved from the Swedish national quality register AuriculA and matched with the Swedish National Patient Register for bleeding complications and background characteristics and the Cause of death register for occurrence and date of death. The rate of bleeding was 1.79 (confidence interval (CI) 95 % 1.66-1.93) per 100 treatment years among all patients. Those with poor warfarin treatment quality had a higher rate of clinically relevant bleeding, both when measured as iTTR below 70 %, 2.91 (CI 95 % 2.61-3.21) or as INR variability over the mean value 0.85, 2.61 (CI 95 % 2.36-2.86). Among those with both high INR variability and low iTTR the risk of clinically relevant bleeding was clearly increased hazard ratio (HR) 3.47 (CI 95 % 2.89-4.17). A similar result was found for all-cause mortality with a HR of 3.67 (CI 95 % 3.02-4.47). Both a low iTTR and a high INR variability increase the risk of bleeding complications or mortality. When combining the two treatment quality indicators patients at particular high risk of bleeding or death can be identified.
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| 9. |
- Siotia, Anjan, et al.
(författare)
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Utility of a whole blood single platelet counting assay to monitor the effects of tirofiban in patients with acute coronary syndromes scheduled for coronary intervention.
- 2006
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 95:6
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to establish the utility of a whole-blood single-platelet counting (WBSPC) assay, a measure of microaggregation, in monitoring the effects of tirofiban, comparing this with optical aggregometry (OA) and the Ultegra TRAP cartridge system (UTC), measures of macroaggregation. Fifty-nine patients with acute coronary syndrome scheduled for coronary angiography +/- angioplasty were studied. WBSPC assay (ADP 0.3-100 microM, Sysmex KX21 analyzer), OA (ADP 20 microM) and UTC were performed: before starting tirofiban; 30 min, 4 and 24 h after starting tirofiban; and 1 and 2 h after stopping tirofiban. Thirty minutes after starting tirofiban, there was substantial inhibition of platelet aggregation (40 +/- 30%; WBSPC, 2 minutes after addition of ADP 30 microM) and this remained stable at 4 and 24 h. OA (86 +/- 17%; inhibition of maximal aggregation, ADP 20 microM) and UTC (93 +/- 7%) showed marked inhibition with less inter-individual variation. There was no significant correlation between OA and UTC results (R(2) = 0.006), but fair correlation between OA and WBSPC results (R(2) = 0.37). Greater inhibition of macroaggregation (OA and UTC) was seen compared to microaggregation (WBSPC) such that WBSPC was more discriminating in the therapeutic range when macroaggregation was often completely inhibited. A WBSPC assay of platelet microaggregation shows promise for monitoring GPIIb/IIIa antagonists.
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| 10. |
- Sjögren, Vilhelm, et al.
(författare)
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Safety and efficacy of well managed warfarin : A report from the Swedish quality register Auricula
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 113:6, s. 1370-1377
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Tidskriftsartikel (refereegranskat)abstract
- The safety and efficacy of warfarin in a large, unselected cohort of warfarin-treated patients with high quality of care is comparable to that reported for non-vitamin K antagonists. Warfarin is commonly used for stroke prevention in atrial fibrillation, as well as for treatment and prevention of venous thromboembolism. While reducing risk of thrombotic/embolic incidents, warfarin increases the risk of bleeding. The aim of this study was to elucidate risks of bleeding and thromboembolism for patients on warfarin treatment in a large, unselected cohort with rigorously controlled treatment. This was a retrospective, registry-based study, covering all patients treated with warfarin in the Swedish national anticoagulation register Auricula, which records both primary and specialised care. The study included 77,423 unselected patients with 100,952 treatment periods of warfarin, constituting 217,804 treatment years. Study period was January 1, 2006 to December 31, 2011. Atrial fibrillation was the most common indication (68%). The mean time in therapeutic range of the international normalised ratio (INR) 2.0-3.0 was 76.5%. The annual incidence of I severe bleeding was 2.24% and of thromboembolism 2.65%. The incidence of intracranial bleeding was 0.37% per treatment year in the whole population, and 0.38% among patients with atrial fibrillation. In conclusion, warfarin treatment where patients spend a high proportion of time in the therapeutic range is safe and effective, and will continue to be a valid treatment option in the era of newer oral anticoagulants.
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