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Lysis Timer: a new sensitive tool to diagnose hyperfibrinolysis in liver transplantation.
Roullet, S, Labrouche, S, Mouton, C, Quinart, A, Nouette-Gaulain, K, Laurent, C, Freyburger, G
Journal of clinical pathology. 2019;(1):58-65
Abstract
AIMS: Diagnosis of hyperfibrinolysis in orthotopic liver transplantation (OLT) remains challenging. Euglobulin clot lysis time (ECLT) is not adapted to clinical situations. ROTEM is specific but seldom sensitive to hyperfibrinolysis. The Lysis Timer assesses 'Global Fibrinolytic Capacity' in citrated plasma (GFC/LT). GFC/LT associates reagents for in vitro triggering of the clot (thrombin and calcium) and its lysis (tissue-plasminogenactivator (t-PA)), turbidity signal acquisition by the Lysis Timer, and dedicated software converting the digital signal into an optical curve. A visual check of the curves was systematic to ascertain the lysis time values calculated by the software. The primary aim of this prospective observational study was to evaluate the ability of GFC/LT to recognise hyperfibrinolysis during OLT. The secondary aim was to compare its results with ROTEM maximum lysis (EXTEM ML) and with standard laboratory tests. METHODS Thirty consecutive adult patients undergoing OLT were included (NCT03012633). Standard laboratory tests, ROTEM, GFC/LT, ECLT and fibrinolysis parameters were assayed at five sample times. RESULTS GFC/LT was correlated with ECLT, plasmin activator inhibitor 1 antigen and activity and t-PA activity (r=0.490, 0.681, 0.643 and -0.359, respectively). Hyperfibrinolysis was defined as ECLT ≤60 min. Receiver operating characteristic curve analysis showed that GFC/LT with a threshold of 31 min detected hyperfibrinolysis with a sensitivity of 0.88 (95% CI 0.73 to 0.96), a specificity of 0.68 (95% CI 0.56 to 0.78) and an area under the curve (AUC) of 0.85 (95% CI 0.74 to 0.94). EXTEM ML >12% did not detect hyperfibrinolysis (sensitivity 0.38 (95% CI 0.24 to 0.55), specificity 0.95 (95% CI 0.86 to 0.99) and AUC 0.60 (95% CI 0.46 to 0.75)). CONCLUSIONS GFC/LT recognised hyperfibrinolysis during OLT with a significant agreement with the other tests of fibrinolysis. TRIAL REGISTRATION NUMBER NCT03012633.
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Impact of a Computerized Antithrombotic Risk Assessment Tool on the Prescription of Thromboprophylaxis in Atrial Fibrillation: Hospital Setting.
Pandya, E, Masood, N, Wang, Y, Krass, I, Bajorek, B
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2018;(1):85-92
Abstract
The computerized antithrombotic risk assessment tool (CARAT) is an online decision-support algorithm that facilitates a systematic review of a patient's stroke risk, bleeding risk, and pertinent medication safety considerations, to generate an individualized treatment recommendation. The CARAT was prospectively applied across 2 hospitals in the greater Sydney area. Its impact on antithrombotics utilization for thromboprophylaxis in patients with nonvalvular atrial fibrillation was evaluated. Factors influencing prescribers' treatment selection were identified. The CARAT recommended a change in baseline therapy for 51.8% of patients. Among anticoagulant-eligible patients (ie, where the risk of stroke outweighed the risk of bleeding) using "nil therapy" or antiplatelet therapy at baseline, the CARAT recommended an upgrade to warfarin in 60 (30.8%) patients. For those in whom the bleeding risk outweighed the stroke risk, the CARAT recommended a downgrade from warfarin to safer alternatives (eg, aspirin) in 37 (19%) patients. Among the "most eligible" (ie, high stroke risk, low bleeding risk, no contraindications; n = 75), the CARAT recommended warfarin for all cases. Discharge therapy observed a marginal increase in anticoagulation prescription in eligible patients (n = 116; 57.8% vs 64.7%, P = .35) compared to baseline. Predictors of warfarin use (vs antiplatelets) included congestive cardiac failure, diabetes mellitus, and polypharmacy. The CARAT was able to optimize the selection of therapy, increasing anticoagulant use among eligible patients. With the increasing complexity of decision-making, such tools may be useful adjuncts in therapy selection in atrial fibrillation. Future studies should explore the utility of such tools in selecting therapies from within an expanded treatment armamentarium comprising the non-vitamin K antagonist oral anticoagulants.
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Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves.
Sondergaard, L, De Backer, O, Kofoed, KF, Jilaihawi, H, Fuchs, A, Chakravarty, T, Kashif, M, Kazuno, Y, Kawamori, H, Maeno, Y, et al
European heart journal. 2017;(28):2201-2207
Abstract
AIMS: Four-dimensional volume-rendered computed tomography (4DCT) has demonstrated instances of hypo-attenuating leaflet thickening (HALT) with or without hypo-attenuation affecting motion (HAM) after transcatheter and surgical aortic valve implantation (TAVI, SAVR). The temporal pattern of evolution of these phenomena is uncertain. METHODS AND RESULTS The SAVORY registry enrolled patients treated by TAVI (n = 75) or SAVR (n = 30) with two 4DCT scans fully interpretable for HALT and HAM as well as unchanged anti-thrombotic medication between the scans. Logistic regression analysis was performed to examine the evolution of HALT and HAM while accounting for demographic and baseline variables, timing of both CT scans, valve type and antithrombotic therapy. The analysis population consisted of 84 patients, in whom first and second CT scans were performed at 140 ± 152 days and 298 ± 141 days after valve implantation, respectively. Hypo-attenuating leaflet thickening was noted in 32 patients (38.1%), with HAM in 17 (20.2%). Both findings were dynamic, showing progression in 13 (15.5%) and regression and 9 (10.7%) patients. Compared with antiplatelet therapy, progression was less likely among patients on oral anticoagulation with vitamin-K antagonists or non-VKA oral anticoagulants (odds ratio: 0.014, P = 0.036). Maintenance on chronic oral anticoagulation was not a significant predictor of regression. These findings were similar for both transcatheter and surgical bioprosthetic aortic valves. No patients developed symptoms of valve dysfunction and leaflet thickening was not clearly associated with any clinical events. CONCLUSIONS Subclinical leaflet thrombosis is a common finding after TAVI and SAVR, and may progress from normal leaflet over HALT to the more severe HAM. The phenomenon can develop and regress at variable intervals after valve implantation. Anticoagulants may have a protective effect against the development of HALT, but HALT can also regress without anticoagulation therapy. REGISTERED AT CLINICALTRIALS.GOV: NCT02426307.
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Deterioration of renal function at stent implantation can predict long-term outcome after stent thrombosis.
Kanic, V, Penko, M, Naji, FH, Ekart, R, Kanic, Z, Dinevski, D, Hojs, R
Wiener klinische Wochenschrift. 2015;:S181-6
Abstract
OBJECTIVES The aim of the study was to examine the possible influence of minor deterioration of the renal function after stent implantation not fulfilling the criteria for acute kidney injury on long-term outcomes after stent thrombosis (ST). BACKGROUND Decreased renal function (DRF) is associated with an increased risk for worse outcome after percutaneous coronary intervention. There is no data if the deterioration of renal function after stent implantation influences the prognosis after ST. If so patients with a higher risk for worse outcome after ST could be identified already at the time of stent implantation. METHODS Data from 4824 consecutive patients treated with percutaneous coronary intervention in our center was recorded from March 2004 to April 2010. We excluded patients with acute kidney injury at stent implantation and 86 of them with ST without acute kidney injury at stent implantation were involved in the study. They were prospectively followed until December 2012 for 50.2 ± 28.1 months. Only patients with definite ST were included in the study. The Academic Research Consortium definition of ST was used. Data on death, myocardial infarction, and repeated percutaneous or operative revascularization after ST were ascertained from the hospital database, by phone or with clinical examinations. The outcomes after definite ST were compared in patients with and without deterioration of renal function after stent implantation (DRFafterSI). RESULTS During the observational period patients with DRFafterSI had a higher mortality rate after ST than patients without DRFafterSI (35.1 vs. 10.3 %; p <0.019). The incidence of major adverse cardiac events (major adverse coronary event (MACE)-death, myocardial infarction, repeated revascularization) rate after ST was similar in both groups (66.1 % with DRFafterSI vs. 55.2 % without DRFafterSI). The prevalence of myocardial infarction was also similar in both groups (31.6 vs. 34.5 %) as was the revascularizations rate (43.9 vs. 48.3 %). Death was predicted by DRFafterSI (adjusted hazard ratio (HR) 3.96; 95 % confidence interval (CI) 1.11 to 14.10; p <0.034) and age > 75 years (adjusted HR 2.85: 95 % CI 1.12-7.30; p = 0.029). We could not find any predictor for MACE. CONCLUSIONS Even more subtle DRFafterSI (not fulfilling the criteria for acute kidney injury) at stent implantation were associated with higher long-term mortality after ST. Especially at risk were patients older than 75 years at stent implantation. DRFafterSI and age more than 75 years pointed out the group of patients with a high risk for death after ST already at the time of stent implantation. The best treatment option for preventing ST in these patients is still to be determined. Until then, we must pay a special attention to proper patients' preparation and hydration to avoid DRFafterSI.
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In vitro comparison of the novel, dual-acting FIIa/FXa-inhibitor EP217609C101, unfractionated heparin, enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis.
Kaeberich, A, Raaz, U, Vogt, A, Maedgefessel, L, Neuhart, E, Krezel, C, Drouget, L, Hauroeder, B, Buerke, M, Werdan, K, et al
Journal of thrombosis and thrombolysis. 2014;(2):118-30
Abstract
Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 μg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 μg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 μg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 μg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 μg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.
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Detection of the full-length transcript variant for neurokinin-1 receptor in human whole blood associated with enhanced reinforcement of clot by substance-P.
Azma, T, Sugimoto, Y, Kinoshita, H, Ito, T, Tsukamoto, M, Hoshijima, H, Nakao, M, Kikuchi, H
Journal of thrombosis and thrombolysis. 2012;(4):329-37
Abstract
We have recently reported that a neurotransmitter for pain, substance-P (SP), promotes platelet-dependent clot formation through neurokinin-1 receptors (NK1Rs), in which leukocytes appear to be involved (J Thromb Thrombolysis 2009;27:280-6). Two naturally occurring splice isoforms of NK1R with different signal transduction potency, namely the full-length and the truncated NK1Rs are identified. It is known that human leukocytes express truncated NK1Rs, while in vivo expression of the full-length NK1R has not yet been fully clarified. Modulatory effects of alternative splicing for NK1Rs on clot formation also remain to be evaluated. Expression of the transcript variant mRNA for NK1Rs in human whole blood (n = 20) was evaluated by real-time reverse transcription polymerase chain reaction (RT-PCR). A 15 min time series of the strength of clot, formed after reloading of calcium in citrated whole blood with or without SP (10 nM) and a NK1R antagonist Spantide (1 μM), was measured by using oscillating-probe viscoelastometry. The full-length transcript variant was detected in 5 samples among 20. SP significantly increased the clot strength while Spantide suppressed the SP-derived change. The extent of modulation by SP/NK1R pathway in a subgroup with expression of the full-length transcript variant was three times as potent as those in another subgroup without expression. We conclude that expression of the full-length transcript variant for NK1R can be detected in human whole blood and that such expression is associated with the enhanced reinforcement of clot by SP. Further study is required to nominate this mRNA as a biomarker for prothrombotic risks in painful conditions such as perioperative period.
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Effects of thrombolytic agents on tympanostomy tubes occluded by blood clots.
Orestes, MI, Fileta, B, Haymes, S, Brietzke, SE
Archives of otolaryngology--head & neck surgery. 2011;(12):1228-31
Abstract
OBJECTIVE To investigate the efficacy of various topical applications in opening a clotted tympanostomy tube (TT) using an in vitro model. DESIGN In vitro clinical trial. INTERVENTIONS Fresh human blood was allowed to clot in the lumen of TTs. Seven agents were tested: 0.9% saline (control), 1-mg/mL alteplase, 100-U/mL unfractionated heparin, 3% hydrogen peroxide (H(2)O(2)), 3% acetic acid, 5% acetic acid, and a mixture of 3% H(2)O(2) and 3% acetic acid. Each agent was added twice a day for 14 days to TTs that were incubated and humidified to simulate ear canal conditions. The tubes were analyzed with binocular microscopy to determine the status of the obstruction. RESULTS A total of 16 trials per agent, including a saline control, were performed. The saline control, alteplase, and heparin failed to open any TTs in any of the trials. Compared with the control, H(2)O(2) also was not effective (P = .23). Acetic acid was increasingly effective, with a 3% concentration completely clearing 5 of 16 tubes and a 5% concentration completely clearing 11 of 16 tubes (P = .006). The addition of 3% H(2)O(2) to 3% acetic acid did not significantly increase clearance (P = .21). CONCLUSIONS Thrombolytic agents and H(2)O(2) were not effective in resolving TTs that were clotted with blood in an in vitro environment simulating the ear canal. Increasing concentrations of acetic acid are increasingly effective in this capacity.
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Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
Agnelli, G, Gallus, A, Goldhaber, SZ, Haas, S, Huisman, MV, Hull, RD, Kakkar, AK, Misselwitz, F, Schellong, S, ,
Circulation. 2007;(2):180-7
Abstract
BACKGROUND An effective and safe oral anticoagulant that needs no monitoring for dose adjustment is urgently needed for the treatment of diseases that require long-term anticoagulation. Rivaroxaban (BAY 59-7939) is an oral direct factor Xa inhibitor currently under clinical development. METHODS AND RESULTS This randomized, parallel-group phase II trial in patients with proximal deep-vein thrombosis explored the efficacy and safety of rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily compared with enoxaparin 1 mg/kg BID followed by vitamin K antagonist. Each treatment was administered for 12 weeks. The primary efficacy end point was an improvement in thrombotic burden at day 21 (assessed by quantitative compression ultrasonography; > or = 4-point improvement in thrombus score) without recurrent symptomatic venous thromboembolism or venous thromboembolism-related death. The primary safety end point was major bleeding during 12 weeks of treatment. Outcomes were adjudicated centrally without knowledge of treatment allocation. The primary efficacy end point was achieved in 53 (53.0%) of 100, 58 (59.2%) of 98, 62 (56.9%) of 109, and 49 (43.8%) of 112 patients receiving rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily, respectively, compared with 50 (45.9%) of 109 patients treated with enoxaparin/vitamin K antagonist. There was no significant trend in the dose-response relationship between rivaroxaban BID and the primary efficacy end point (P=0.67). Major bleeding was observed in 1.7%, 1.7%, 3.3%, and 1.7% of patients receiving rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily, respectively. There were no major bleeding events with enoxaparin/vitamin K antagonist. CONCLUSIONS Results of this proof-of-concept and dose-finding study support phase III evaluation of the orally active direct factor Xa inhibitor rivaroxaban, because efficacy and safety were apparent in the treatment of proximal deep-vein thrombosis across a 3-fold range of fixed daily dosing.
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Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.
Suh, JW, Koo, BK, Zhang, SY, Park, KW, Cho, JY, Jang, IJ, Lee, DS, Sohn, DW, Lee, MM, Kim, HS
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2006;(12):1715-22
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Abstract
BACKGROUND Clopidogrel is a prodrug requiring metabolism by cytochrome P450 3A (CYP3A) isoenzymes, including CYP3A5, in order to be active. It is controversial whether clopidogrel interacts with CYP3A inhibitors. We investigated the influence of CYP3A5 polymorphism on the drug interaction of clopidogrel. METHODS In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 non-expressor genotype (*3 allele) and 16 who had the CYP3A5 expressor genotype (*1 allele) with and without pretreatment with itraconazole, a potent CYP3A inhibitor. A platelet aggregation test was performed at baseline, 4 hours, 24 hours and 6 days after clopidogrel administration. In phase 2, we compared clinical outcomes of 348 patients treated with clopidogrel after successful coronary angioplasty with bare-metal stent implantation according to their CYP3A5 genotype; the primary end point was a composite of atherothrombotic events (cardiovascular death, myocardial infarction and non-hemorrhagic stroke) within 1 and 6 months after stent implantation. RESULTS In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5 expressor genotype than among those with the non-expressor genotype: 24.9% (standard deviation [SD] 13.9%) v. 6.2% (SD 13.5%) at 4 hours (p < 0.001); 27.7% (SD 16.5%) v. 2.5% (SD 8.3%) at 24 hours (p < 0.001); and 33.5% (SD 18.6%) v. 17.8% (SD 13.8%) at day 7 (p < 0.01). In phase 2, atherothrombotic events occurred more frequently within 6 months after stent implantation among the patients with the non-expressor genotype than among those with the expressor genotype (14/193 v. 3/155; p = 0.023). Multivariable analysis showed that the CYP3A5 polymorphism was a predictor of atherothrombotic events in clopidogrel users. INTERPRETATION People with the CYP3A5 non-expressor genotype are vulnerable to drug interactions between clopidogrel and CYP3A inhibitors. This phenomenon may be associated with worse outcomes in patients with the non-expressor genotype who are given clopidogrel after coronary angioplasty and implantation of bare-metal stents.
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Effects of different progestin regimens in hormone replacement therapy on blood coagulation factor VII and tissue factor pathway inhibitor.
Bladbjerg, EM, Skouby, SO, Andersen, LF, Jespersen, J
Human reproduction (Oxford, England). 2002;(12):3235-41
Abstract
BACKGROUND Long-term hormone replacement therapy (HRT) reduces cardiovascular risk, but an early increased risk was reported in women with coronary heart disease. In such women the arterial intima can express tissue factor, and changes in coagulation factor VII (factor VII) and tissue factor pathway inhibitor (TFPI) may be deleterious. METHODS We measured factor VII clotting activity, activated factor VII, and concentrations of factor VII and TFPI during 12 months in healthy post-menopausal women randomized to: (i). cyclic oral estrogen/progestin (n = 25); (ii). long-cycle oral estrogen/quarterly progestin (n = 32); (iii). continuous oral estrogen/progestin (n = 21); (iv). continuous oral estrogen/intrauterine progestin (n = 22); (v). no HRT (n = 26). Blood was collected at baseline, 3, 6 and 12 months. Additional sampling was done before progestin intake in the long cycle group. RESULTS No variations were observed in the reference group. There was a substantial decrease in TFPI concentrations in the HRT groups irrespective of the type of progestin. In women receiving long-cycle treatment, all factor VII measures increased during the unopposed estrogen periods, and the increase was reversed after progestin intake. The integrated response, AUC, for TFPI was significantly lower in the HRT groups compared with the reference group. CONCLUSION The observed changes may increase the early thrombotic risk associated with HRT use.