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Concept: Prothrombin time

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Oral anticoagulant therapy is used to prevent thrombosis in patients with atrial fibrillation (AF), venous thrombosis and prosthetic heart valves. The introduction of new therapies emphasizes the need to discern the best practice for the patients remaining on warfarin treatment. This study compares patient characteristics and therapeutic control in two settings managing warfarin treatment: Swedish primary health care centers (PHCC) and specialized anticoagulation clinics (ACC).

Concepts: Medicine, Stroke, Atrial fibrillation, Thrombosis, Warfarin, Anticoagulant, Heparin, Prothrombin time

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BACKGROUND: Laboratory tests to assess novel oral anticoagulants (NOACs) are under evaluation. Routine monitoring is unnecessary, but under special circumstances bioactivity assessment becomes crucial. We analyzed the effects of NOACs on coagulation tests and the availability of specific assays at different laboratories.METHODS: Plasma samples spiked with dabigatran (Dabi; 120 and 300 μg/L) or rivaroxaban (Riva; 60, 146, and 305 μg/L) were sent to 115 and 38 European laboratories, respectively. International normalized ratio (INR) and activated partial thromboplastin time (APTT) were analyzed for all samples; thrombin time (TT) was analyzed specifically for Dabi and calibrated anti-activated factor X (anti-Xa) activity for Riva. We compared the results with patient samples.RESULTS: Results of Dabi samples were reported by 73 laboratories (13 INR and 9 APTT reagents) and Riva samples by 22 laboratories (5 INR and 4 APTT reagents). Both NOACs increased INR values; the increase was modest, albeit larger, for Dabi, with higher CV, especially with Quick (vs Owren) methods. Both NOACs dose-dependently prolonged the APTT. Again, the prolongation and CVs were larger for Dabi. The INR and APTT results varied reagent-dependently (P < 0.005), with less prolongation in patient samples. TT results (Dabi) and calibrated anti-Xa results (Riva) were reported by only 11 and 8 laboratories, respectively.CONCLUSIONS: The screening tests INR and APTT are suboptimal in assessing NOACs, having high reagent dependence and low sensitivity and specificity. They may provide information, if laboratories recognize their limitations. The variation will likely increase and the sensitivity differ in clinical samples. Specific assays measure NOACs accurately; however, few laboratories applied them.

Concepts: Positive predictive value, Type I and type II errors, Sensitivity and specificity, Coagulation, Warfarin, Prothrombin time, Partial thromboplastin time

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Background The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. Methods We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. Results At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. Conclusions Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657 .).

Concepts: Pharmacology, Clinical trial, Blood, ClinicalTrials.gov, Warfarin, Dose, Anticoagulant, Prothrombin time

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Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation and likely to be soon approved in Europe for treatment of venous thrombosis. Predictable pharmacokinetics and a reduced risk of intracranial haemorrhage do not negate the potential risk of haemorrhage. Unlike warfarin, there is no reversal agent and measurement of the anticoagulant effect is not ‘routine’. The prothrombin time/international normalised ratio response to dabigatran is inconsistent and should not be measured when assessing a patient who is bleeding or needs emergency surgery. The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT. Commercially available DTI assays provide a quantitative measurement of active dabigatran concentration in the plasma. If a patient receiving dabigatran presents with bleeding: omit/delay next dose of dabigatran; measure APTT and thrombin time (consider DTI assay if available); administer activated charcoal, with sorbitol, if within 2 h of dabigatran ingestion; give tranexamic acid (1 g intravenously if significant bleeding); maintain renal perfusion and urine output to aid dabigatran excretion. Dabigatran exhibits low protein binding and may be removed by dialysis. Supportive care should form the mainstay of treatment. If bleeding is life/limb threatening, consider an additional haemostatic agent. There is currently no evidence to support the choice of one haemostatic agent (FEIBA, recombinant factor VIIa, prothrombin complex concentrates) over another. Choice will depend on access to and experience with available haemostatic agent(s).

Concepts: Blood, Stroke, Atrial fibrillation, Warfarin, Hemostasis, Anticoagulant, Dabigatran, Prothrombin time

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INTRODUCTION: Warfarin treatment with a high time in therapeutic range (TTR) is correlated to fewer complications. The TTR in Sweden is generally high but varies partly depending on local expertise and traditions. A dosing algorithm could minimize variations and increase treatment quality. Here we evaluate the performance of a computerized dosing algorithm. MATERIALS AND METHODS: 53.779 warfarin treated patients from 125 centers using the Swedish national quality registry AuriculA. If certain criteria are met, the algorithm gives one of seven possible dose suggestions, which can be unchanged, decreased or increased weekly dose by 5, 10 or 15%. The outcome evaluated by the resulting INR value was compared between dose suggestions arising from the algorithm that were accepted and those that were manually changed. There were no randomization, and outcomes were retrospectively analyzed. RESULTS: Both the algorithm-based and the manually changed doses had worse outcome if only two instead of three previous INR values were available. The algorithm suggestions were superior to manual dosing regarding percent samples within the target range 2-3 (hit-rate) or deviation from INR 2.5 (mean error). Of the seven possible outcomes from the algorithm, six were significantly superior and one equal to the manually changed doses when three previous INR:s were present. CONCLUSIONS: The algorithm-based dosing suggestions show better outcome in most cases. This can make dosing of warfarin easier and more efficient. There are however cases where manual dosing fares better. Here the algorithm will be improved to further enhance its dosing performance in the future.

Concepts: Algorithm, Warfarin, Dose, Computer-aided design, Outcome, Equals sign, Prothrombin time, Manual transmission

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To compare clinical and safety outcomes of warfarin therapy before and after implementation of a novel patient self-management (PSM) program in which patients received their venipuncture-derived international normalized ratio (INR) results through a secure online messaging system and adjusted their warfarin dosages and follow-up visits according to provided support tools.

Concepts: Patient, Warfarin, According to Jim, Prothrombin time

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In order to develop a promising substitute for heparin, N-succinyl chitosan (NSC) was chemically modified by sulfating agent N(SO(3)Na)(3), which were synthesized with sodium bisulfite and sodium nitrite in aqueous solution. The N-succinyl chitosan sulfates (NSCS) products were characterized by infrared spectroscopy (FT-IR) and (13)C NMR. The degree of substitution (DS) of NSCS depended on the ratio of sulfating agent to N-succinyl chitosan, reaction temperature, reaction time and pH of sulfation agent. N-succinyl chitosan sulfates with DS of 1.97 were obtained under optimal conditions. The in vitro coagulation assay of NSCS was determined by activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) assays. The results showed that NSCS obviously prolonged APTT. The anticoagulant activity strongly depended on DS, molecular weight (M(w)) and concentration of NSCS. The anticoagulant activity of NSCS promoted with the increase of DS and concentration, and NSCS exhibited the best anticoagulant activity with the M(w) of 1.37×10(4).

Concepts: Spectroscopy, Concentration, Chemistry, Warfarin, Heparin, Factor XII, Prothrombin time, Partial thromboplastin time

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In order to increase the yield of prothrombin complex concentrates (PCCs) and to reduce their associated thrombotic risks, the influence of washing conditions on the yield, purity, and balance of coagulation factors (FII, FVII, FIX, and FX), and inhibitor proteins (PC, PS, PZ, and AT [antithrombin]) in PCCs was investigated by orthogonal testing, in which three variables (sodium citrate, NaCl, and pH) and their three levels were selected. It was found that AT yield and purity were extraordinarily low, and at lower NaCl content, the general yield, purity, and balance were higher, lower, and better, respectively; however, the results became contrary at higher NaCl. Moreover, within the investigated levels, NaCl was the first determinant for the yield except AT and the purity except FVII, PC, PS, and AT. Sodium citrate was the first determinant for AT yield and FVII, PS, and AT purity. The yield except FII, PS, and AT decreased and the purity except PC increased with increase of sodium citrate content. Just for PC purity, pH was the first determinant. The effect with pH fluctuation on the yield and purity was characteristically unobvious. The outcome undoubtedly supplies the guidance to further improve PCCs.

Concepts: Blood, Coagulation, Warfarin, Sodium hydroxide, Thrombin, Prothrombin time, Coagulation system, Antithrombin

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BACKGROUND: The clinical variables leading to postoperative thrombotic occlusion of a modified Blalock-Taussig shunt (mBTS) remain elusive. In this investigation, we assess several perioperative variables to determine associations with postoperative in-hospital shunt occlusion. METHODS: We retrospectively reviewed the medical records of infants receiving a mBTS as a first operation between March 1, 2005, and December 31, 2011. Numerous perioperative variables were collected, focusing on those that would increase resistance to blood flow through the shunt or alter coagulation. RESULTS: In all, 207 neonates fit our criteria. In-hospital shunt occlusion occurred in 14 patients (6.8%); 3 patients (21.4%) subsequently died during their hospitalization. Pulmonary atresia/ventricular septal defect with or without major aortopulmonary collateral arteries was the most common diagnosis associated with shunt occlusion (57.1%). Of the collected perioperative variables, pulmonary artery size was significantly associated with shunt occlusion (p = 0.03). Preoperative coagulation values were significantly reduced in those patients who experienced shunt occlusion. Additionally, the immediate postoperative activated partial thromboplastin time was significantly reduced in the occlusion group although values remained well above normal as all infants were treated postoperatively with a heparin infusion. CONCLUSIONS: We found that a patient’s anatomy (pulmonary atresia/ventricular septal defect with or without major aortopulmonary collateral arteries) and the size of the pulmonary artery being shunted had a significant impact in predicting postoperative in-hospital shunt occlusion. These results emphasize that technical skills and a low resistance to blood flow are necessary for successful shunt function. Although some perioperative coagulation values were significantly reduced in infants who were destined to experience shunt occlusion, they would be difficult to detect clinically.

Concepts: Blood, Myocardial infarction, Heart, Artery, Vein, Pulmonary artery, Heparin, Prothrombin time

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OBJECTIVE: In aged-care facilities (ACFs) monitoring of warfarin can be logistically challenging and International Normalised Ratio (INR control) is often suboptimal. We aimed to determine whether an integrated information and communications technology system and the use of point-of-care (POC) monitors by nursing staff could improve the INR control of aged-care facility residents who take warfarin. METHODS: Nursing staff identified residents who were prescribed warfarin in participating ACFs. A computer program (MedePOC) was developed to store and transmit INR results from the ACFs to general practitioners (GPs) for dosage adjustment. Nursing staff received training in the use of the CoaguChek XS point-of-care INR monitor and the MedePOC software. Following a run-in phase, eligible patients were monitored weekly for up to 12 weeks. The primary outcome was the change in the time in therapeutic range (TTR) in the intervention phase compared to the TTR in the 12 months preceding the study. All GPs, nursing staff and patients were surveyed for their experiences and opinions of the project. KEY FINDINGS: Twenty-four patients and 19 GPs completed the trial across six ACFs. The mean TTR for all patients improved non-significantly from 58.9 to 60.6% (P = 0.79) and the proportion of INR tests in range improved non-significantly from 57.1 to 64.1% (P = 0.21). The mean TTR improved in 14 patients (58%) and in these patients the mean absolute improvement in TTR was 23.1%. A post hoc analysis of the INR data using modified therapeutic INR ranges to reflect the dosage adjustment practices of GPs suggested that the intervention did lead to improved INR control. The MedePOC program and POC monitoring was well received by nursing staff. CONCLUSIONS: Weekly POC INR monitoring conducted in ACFs and electronic communication of the results and warfarin doses resulted in non-significant improvements in INR control in a small cohort of elderly residents. Further research involving modification to the communication strategy and a longer follow-up period is warranted to investigate whether this strategy can improve INR control and clinical outcomes in this vulnerable population.

Concepts: Game theory, Better, Improve, Dose, Communication, Prothrombin time, Surveying, Geodesy