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- Agnelli, G, et al.
(author)
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Safety assessment of new antithrombotic agents : Lessons from the EXTEND study on ximelagatran.
- 2009
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In: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 123:3, s. 488-497
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Journal article (peer-reviewed)abstract
- BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.
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- Alström, Ulrica, et al.
(author)
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Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery
- 2009
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In: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 124:5, s. 572-577
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Journal article (peer-reviewed)abstract
- INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.
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- Alström, Ulrica, et al.
(author)
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The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment
- 2007
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In: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 120:3, s. 353-359
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Addition of clopidogrel to patients treated with ASA has been shown to decrease the incidence of in-stent thrombosis after percutaneous coronary interventions. However, it has also been reported that up to 30% of patients do not achieve adequate platelet inhibition from standard dosages of ASA and clopidogrel. There is a demand for reliable methods to measure the individual platelet inhibiting effect of this combination therapy. MATERIALS AND METHODS: The primary aim of the present investigation was to compare three methods for evaluation of the platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thirty patients presenting for coronary angiography/PCI were included. Two patients were excluded due to technical problems. All patients were on 75-100 mg ASA/day for at least 8 days. Blood samples were analysed before and 16 h after a 300 mg clopidogrel bolus dose. The platelet inhibiting effect was measured with (1) Whole blood flow cytometry (17 patients); (2) a bed-side test, Platelet Mapping assay for the thrombelastograph (28 patients); and (3) PFA (Platelet function analyser) -100 (26 patients). RESULTS: With flow cytometry, the percentage of platelets expressing P-selectin (p=0.03) on their surface decreased significantly after the bolus dose of clopidogrel. There was also a reduction of platelets binding fibrinogen when stimulated with ADP. A significantly (p=0.002) increased platelet inhibition could also be demonstrated with Platelet Mapping. PFA-100 could not measure any significant platelet inhibiting effect of clopidogrel. CONCLUSION: A significant platelet inhibition could be demonstrated with flow cytometry and the Platelet Mapping assay, but not with PFA-100. However, levels of response for the individual patient with these three methods were inconsistent. Further studies are needed to evaluate how the results correlate to the clinical risk of thrombosis and bleeding.
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- Amisten, Stefan, et al.
(author)
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Gene expression profiling for the identification of G-protein coupled receptors in human platelets
- 2008
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 122:1, s. 47-57
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Journal article (peer-reviewed)abstract
- INTRODUCTION AND MATERIALS AND METHODS: G-protein coupled receptors (GPCRs) play an important role in platelet aggregation. To identify new platelet GPCRs, a platelet gene expression profile was generated and validated using quantitative real-time PCR. RESULTS: In total, mRNA of 28 GPCR genes was detected in human platelets. The 12 most abundant platelet GPCR transcripts were: thrombin receptor PAR1 (1865+/-178%), ADP receptor P2Y(12) (459+/-88%), succinate receptor 1 (257+/-48%), ADP receptor P2Y(1) (100%), orphan P2RY(10) (68.2+/-3.3%), lysophosphatidic acid receptors GPR23 (48.2+/-11%) and GPR92 (26.1+/-3.3%), adrenergic receptor alpha(2A) (18.4+/-4.4%), orphan EBI2 (6.31+/-0.42), adenosine receptors A(2A) (2.94+/-0.24%) and A(2B) (2.88+/-0.16%) and lysophosphatidic acid receptor LPA(1) (2.59+/-0.39%) (% relative to the chosen calibrator P2Y(1)). A surprising G-protein coupled receptor redundancy was found: two ADP receptors (P2Y(1) and P2Y(12)), three adenosine receptors (A(2A), A(2B), and A(1)), four lysophosphatidic acid receptors (LPA(1), LPA(3), GPR23 and GPR92), two l-glutamate receptors (mGlu(3) and mGlu(4)) and two serotonin receptors (5-HT(1F) and 5-HT(4)). The adenosine receptor A(2B) gene expression was validated with protein expression and functional studies. Western blot confirmed A(2B) receptor protein expression and platelet flow cytometry demonstrated inhibition of the effect of NECA by the adenosine A(2B)-antagonist MRS1754. CONCLUSIONS: We have detected several GPCRs not previously known to be expressed in platelets, including a functional adenosine A(2B) receptor. The findings could improve our understanding of platelet aggregation and provide new targets for drug development.
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- Berntorp, Erik
(author)
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Erik von Willebrand.
- 2007
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 120, s. 3-4
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Journal article (peer-reviewed)
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| 8. |
- Berntorp, Erik, et al.
(author)
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The von Willebrand Disease Prophylaxis Network (vWD PN): Exploring a treatment concept.
- 2006
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 18, s. 19-22
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Journal article (peer-reviewed)abstract
- The von Willebrand Disease Prophylactic Network (vWD PN) has been initiated to study the natural history of vWD bleeding, and to prospectively study the role of von Willebrand Factor (vWF) concentrate prophylaxis in vWD. Patients with all types of vWD in need of treatment with vWF concentrate will be enrolled into the study. Quality of life will be measured and safety and efficacy will be monitored at pre-determined intervals. Between February 2005 and July 18, 2005, 62 investigators from Europe and North America were participating in the vWD PN, and 61 have submitted census data. A total 5343 patients have been identified for enrolment, and of these, 991 patients were treated with plasma-derived products in the preceding 12 months, and 99 patients have received prophylaxis, predominantly for joint-related bleeds. The vWD PN aims to further elucidate the role of vWF concentrate prophylaxis in vWD and to identify patients most Likely to benefit from prophylaxis.
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| 10. |
- Bhiladvala, Pallonji, et al.
(author)
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Early identification of acute myocardial infarction by activated protein C-protein C inhibitor complex.
- 2006
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 118:Aug 10, s. 213-219
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Journal article (peer-reviewed)abstract
- Introduction: Increased coagulation activity due to coronary thrombosis in a ruptured plaque should result in activation of the protein C anticoagulant system with formation of complexes between activated protein C (APC) and,the protein C inhibitor (PCI), which reflects coagulation activity. We hypothesized that elevated APC-PCI concentration might allow earlier detection of ongoing myocardial infarction than traditional biochemical markers. We have evaluated a newly devised immunofluorimetric assay for measuring plasma concentration of APC-PCI complexes among patients with suspected acute coronary syndrome. Materials and methods: Blood samples were taken from 340 patients (median 71 years, range 31-97) with suspected acute coronary syndrome at first presentation in the emergency department. Electrocardiogram was recorded and APC PCI, Troponin I and Creatine kinase-MB concentrations were repeatedly measured 3 times at 6 h interval. Results: The 74 patients who were eventually diagnosed with myocardial infarction had a higher median level of APC-PCI complex than those Without myocardial damage; 0.27 vs. 0.20 mu g/L (p = 0.001). In a multivariate regression model, APC-PCI level in the fourth quartile (> 0.32 mu g/L) independently predicted myocardial infarction with an odds ratio of 3.7 (95% CI 1.4-9.6, p < 0.01). Conclusion: Early APC-PCI elevation can be detected among patients with a normal first Troponin I and non-ST-elevation myocardial infarction and provides additional risk assessment in acute coronary syndrome. (c) 2005 Published by Elsevier Ltd.
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