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  • Föregående 123[4]5Nästa
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  • Oldgren, Jonas, 1964-, et al. (författare)
  • Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients
  • 2007
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 28:6, s. 699-704
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been suggested as an independent predictor of cardiovascular events in epidemiological studies. We sought to evaluate Lp-PLA(2) as a risk factor for future cardiovascular events in patients with acute coronary syndromes (ACS) and to elucidate the relationship between Lp-PLA(2) and other known risk markers in ACS patients and healthy control subjects. METHODS AND RESULTS: Blood samples were obtained at randomization in a random subset of ACS patients in the FRISC II (n = 1362) and GUSTO IV (n = 904) studies and in 435 apparently healthy controls of similar age and gender. Median Lp-PLA(2) (mass) levels were 305 ng/mL (FRISC II), 373 ng/mL (GUSTO IV), and 254 ng/mL (healthy controls). Time delay from symptom onset did not influence Lp-PLA(2) levels. In the FRISC II patients and healthy controls, Lp-PLA(2) was significantly correlated with cholesterol (r = 0.3), low-density lipoprotein (r = 0.4 and r = 0.3, respectively), and C-reactive protein (r = 0.08 and r = 0.1, respectively), all P < 0.01. Lp-PLA(2) was not correlated with age, interleukin-6, troponin T, or NT-proBNP in any of the three cohorts. There was no difference in the composite of death and myocardial infarction at 30 days (GUSTO IV) or 180 days (FRISC II) in relation to low, middle, and top tertiles of Lp-PLA(2) at randomization. In FRISC II, the 1 year mortality was 4.2, 4.2, and 4.8% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.8. In GUSTO IV, 1 year mortality was 7.0, 8.3, and 9.6% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.5. CONCLUSION: ACS patients had higher Lp-PLA(2) levels than healthy controls. Lp-PLA(2) was significantly correlated to lipid levels but only weakly correlated or unrelated to other well-established risk markers in ACS. The risk of future cardiovascular events or mortality was not related to Lp-PLA(2) levels in ACS patients. The biological role of Lp-PLA(2) and its role as a risk marker in ACS patients still remain unclear.
  • Oldgren, Jonas, 1964-, et al. (författare)
  • Xa inhibition and coagulation activity : the influence of prolonged dalteparin treatment and gender in patients with acute coronary syndrome and healthy individuals
  • 2008
  • Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 155:3, s. 493.e1-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: We evaluated coagulation activity in relation to gender in patients with acute coronary syndromes and in healthy individuals of similar age, and related coagulation activity to levels of Xa inhibition during dalteparin treatment. METHODS: Serial blood samples were obtained from 555 (172 women) of 2267 patients in the Scandinavian FRISC II study, and a single sample in 457 (151 women) apparently healthy age- and sex-matched individuals. After randomization, all patients received dalteparin 120 IU/kg s.c. (maximum 10,000 IU) twice daily for 5 to 7 days inhospital and thereafter placebo (n = 285) or sex- and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months. RESULTS: Before randomization, 96% of the patients had open-label anticoagulation with unfractionated heparin or dalteparin. Therapeutic anti-Xa levels (> 0.5 IU/mL) were found in 74%, 55%, 58%, and 33% of the dalteparin-treated patients at randomization, 2 days, 4 to 7 weeks, and 3 months, respectively, and were significantly related to lower levels of coagulation activity, ie, factor VIIa, prothrombin fragment 1+2, and D-dimer, during prolonged treatment. Female patients had higher anti-Xa levels than men at randomization (median 0.69 vs 0.60 IU/mL, P = .01) and at 2 days (0.65 vs 0.59 IU/mL, P < .001). Female patients had also significantly higher levels of all 3 coagulation markers at randomization, 2 days, 4 to 7 weeks, and 3 and 6 months. Similarly, healthy women had higher prothrombin fragment 1+2 levels (median 1.19 vs 0.94 nmol/L) and D-dimer levels than men (26 vs 21 microg/L) (both P < .001). CONCLUSIONS: Despite weight-adjusted dosing, female patients reached higher anti-Xa levels, suggesting increased sensitivity to dalteparin treatment. Healthy women and female patients also had higher coagulation activity, which might increase the risk of thrombus formation. The large proportion of patients with subtherapeutic anti-Xa during prolonged dalteparin treatment may reflect poor compliance and could thus contribute to the gradual loss of clinical efficacy.
  • Siegbahn, Agneta, et al. (författare)
  • Regulation of chemotaxis by the cytoplasmic domain of tissue factor
  • 2005
  • Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 93:1, s. 27-34
  • Tidskriftsartikel (refereegranskat)abstract
    • We previously demonstrated that FVIIa bound to tissue factor (TF) induces a hyperchemotactic response towards PDGF-BB. The aim of the present study was to investigate the role of the cytoplasmic domain of TF in cell migration. Porcine aortic endothelial (PAE) cells expressing human PDGF beta-receptors (PAE/PDGFRbeta) were transfected for expression of human wildtype TF (PAE/PDGFRbeta,TF), a construct lacking the cytoplasmic domain (PAE/PDGFRbeta,TFDeltacyto), a construct with alanine replacement of serine 258 (PAE/PDGFRbeta,TFS258A), or a construct with alanine replacement of serine 253, 258 and 263 in the cytoplasmic domain (PAE/PDGFRbeta,TF3SA). All stably transfected cell lines expressed functional TF. Chemotaxis was analyzed in a modified Boyden chamber assay. PAE/PDGFRbeta,TF cells stimulated with FVIIa migrated towards a 100-fold lower concentration of PDGF-BB than in the absence of FVIIa, however, hyperchemotaxis was not seen in PAE/PDGFRbeta,TFDeltacyto cells. PAE/PDGFRbeta/TFS258A and PAE/PDGFRbeta,TF3SA cells responded to low levels of PDGF-BB, but migrated a significantly shorter distance than PAE/PDGFRbeta,TF cells. Thus, hyperchemotaxis towards PDGF-BB is likely to depend in part on phosphorylation of the cytoplasmic domain of TF. We conclude that the cytoplasmic domain of TF plays a pivotal role in modulating cellular migration response. Our results suggest that the FVIIa/TF complex mediates intracellular signaling by alternative signal transduction pathway(s).
  • Siegbahn, Agneta, et al. (författare)
  • TF/FVIIa transactivate PDGFRbeta to regulate PDGF-BB-induced chemotaxis in different cell types : involvement of Src and PLC
  • 2008
  • Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 28:1, s. 135-41
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: We have previously reported the potentiation of PDGF-BB-induced chemotaxis of fibroblasts, vascular smooth muscle cells, and endothelial cells by FVIIa. Here we studied the role of TF/FVIIa and the induced signaling pathways in regulation of chemotaxis of human monocytes, fibroblasts, and porcine aorta endothelial cells. METHODS AND RESULTS: Human monocytes were obtained by using Ficoll-Paque gradient and the MACS system (for highly purified population), fibroblasts and PAE cells have been characterized previously. Inhibitors of selected signaling intermediates were used, and the effect of TF/FVIIa on the migratory response of all cells to chemotactic agents was analyzed. The induced signaling was studied by immunoprecipitation and Western blotting. TF/FVIIa complex selectively enhanced PDGF-BB-induced chemotaxis in a Src-family, PLC, and PAR-2-dependent manner. Using PAE cells we identified c-Src and c-Yes as the Src-family members activated by TF/FVIIa. We report for the first time the PAR-2 and Src family-dependent transactivation of PDGFRbeta by TF/FVIIa involving phosphorylation of a subset of PDGFRbeta tyrosines. CONCLUSIONS: The described transactivation is a likely mechanism of TF/FVIIa-mediated regulation of PDGF-BB-induced chemotaxis. Similar behavior of 3 principally different cell types in our experimental setup may reflect a general function of TF in regulation of cell migration.
  • Skagius, Elisabeth, et al. (författare)
  • Activated coagulation in patients with shock due to ruptured abdominal aortic aneurysm
  • 2008
  • Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 35:1, s. 37-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Ruptured abdominal aortic aneurysm is associated with a high operative mortality. Postoperative thrombosis related complications are common, a possible mechanism being activation of the coagulation system and endothelial stimulation. The aim of the present study was to investigate the coagulation activity preoperatively in patients with ruptured and nonruptured abdominal aortic aneurysm in relation to the clinical outcome with special regard to the influence of shock. Methods. Ninety-five patients with repair of infrarenal aortic aneurysm and forty-one controls without aneurysm matched by age, gender and smoking habits were studied. Thrombin-antithrombin (TAT), prothrombin fragment 1 + 2 (F 1 + 2), and von Willebrand factor antigen (vWFAg) were measured. Results. There were significantly higher levels of TAT, F 1 + 2, and vWFAg in patients operated for ruptured compared to nonruptured abdominal aortic aneurysm. The highest level of TAT and F 1 + 2 were detected in patients with rupture and shock. Conclusion. The present data indicate a state Of activated coagulation in patients with ruptured abdominal aortic aneurysm which is reinforced by shock.
  • Skagius, E, et al. (författare)
  • Fibrinolysis in patients with abdominal aortic aneurysm with special emphasis on rupture and shock
  • 2007
  • Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 6:1, s. 147-150
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  • Thulin, Åsa, et al. (författare)
  • Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein
  • 2009
  • Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 7:11, s. 1792-1802
  • Tidskriftsartikel (refereegranskat)abstract
    • The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain.Using a combination of immunohistochemistry and massspectrometry, we here provide biochemical evidence for thepresence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons.Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro–activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn2+.Previous studies have shown that zinc-dependent bindingof the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis.We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor,which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.
  • Varenhorst, Christoph, et al. (författare)
  • Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin
  • 2009
  • Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 157:3, s. 562.e1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Variability in response to thienopyridines has led to the development of point-of-care devices to assess adenosine diphosphate (ADP)-induced platelet aggregation. These tests need to be evaluated in comparison to reference measurements of P2Y(12) function during different thienopyridine treatments. METHODS: After a run-in on 75 mg aspirin, 110 subjects were randomized to double-blind treatment with clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD. Antiplatelet effects were evaluated by VerifyNow P2Y12 (VN-P2Y12) device (Accumetrics, San Diego, CA), vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, and light transmission aggregometry (LTA). Prasugrel's and clopidogrel's active metabolite concentration were also determined. RESULTS: Dose- and time-dependent inhibition of P2Y(12) was evident with VN-P2Y12. There was strong correlation with VN-P2Y12 and VASP or LTA for all treatments through a wide range of P2Y(12) function. At high levels of P2Y(12) inhibition, platelet function measured by VN-P2Y12 was maximally inhibited and could not reflect further changes seen with VASP or LTA methods. Correlation was also observed between exposure to clopidogrel's active metabolite and VN-P2Y12 during MD and LD, whereas it was observed only with prasugrel MD. CONCLUSION: The VN-P2Y12 correlated strongly with inhibition of P2Y(12) function, as measured with either VASP or LTA. VN-P2Y12 also correlated to exposure to the active metabolite of prasugrel and clopidogrel up to levels associated with assumed saturation of the P2Y(12) receptor.
  • Varenhorst, Christoph, 1977-, et al. (författare)
  • Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease
  • 2009
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:14, s. 1744-1752
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Methods and results Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Conclusion Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel.
  • Wallentin, Lars, 1943-, et al. (författare)
  • Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease
  • 2008
  • Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:1, s. 21-30
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.
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