Thrombosis and haemostasis
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Emicizumab, a humanised bispecific antibody recognising factors (F) IX/IXa and X/Xa, can accelerate FIXa-catalysed FX activation by bridging FIXa and FX in a manner similar to FVIIIa. However, details of the emicizumab-antigen interactions have not been reported so far. In this study, we first showed by surface plasmon resonance analysis that emicizumab bound FIX, FIXa, FX, and FXa with moderate affinities (KD = 1.58, 1.52, 1.85, and 0.978 µM, respectively). ⋯ The simulation also predicted that at 10.0-100 µg/ml of emicizumab-levels shown in a previous study to be clinically effective-the majority of plasma FIX, FX, and emicizumab would exist as monomers. In conclusion, emicizumab binds FIX/FIXa and FX/FXa with micromolar affinities at their EGF-like domains. The KD-based simulation predicted that the antigen-bridging ternary complex formed in circulating plasma would correlate with emicizumab's cofactor activity, and the majority of FIX and FX would be free and available for other coagulation reactions.
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Idarucizumab is licensed for emergency reversal of dabigatran. A single 5 g dose is usually sufficient, but higher doses may sometimes be required and optimum dosing has not been defined. It was the aim of this study to investigate the effect of idarucizumab, given once or as a split dose, after double trauma in pigs anticoagulated with dabigatran. ⋯ Analysis of dabigatran plasma concentrations showed that equimolar concentrations of idarucizumab are necessary to bind all dabigatran and achieve sufficient thrombin generation. At sufficient doses, idarucizumab rapidly reduced blood loss and improved survival in this lethal porcine model of double trauma with dabigatran anticoagulation. In clinical practice, should bleeding continue after initial treatment with the approved 5 g dose of idarucizumab, a second dose may potentially be effective to control bleeding caused by redistribution of unbound dabigatran.
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Oral anticoagulation (OAC) is highly effective preventing stroke and mortality in AF, but withdrawal is common in the elderly, when high bleeding risk and when are difficulties achieving an optimal time in therapeutic range (TTR). We analysed the rate of OAC cessation, predisposing factors to cessation and the relation to clinical outcomes in a large 'real world' cohort of AF patients over a long follow-up period. Consecutive non-valvular AF outpatients clinically stables for six months were recruited. ⋯ Independent predictors of OAC cessation were age ≥80 (HR 2.29; 1.60-3.29), previous coronary artery disease (HR 0.32; 0.15-0.71), major bleeding (HR 5.00; 3.49-7.15), heart failure (HR 2.38; 1.26-4.47), cancer (HR 5.24; 3.25-8.44) and renal impairment developed during follow-up (HR 2.70; 1.26-5.75). In conclusion, in non-valvular AF patients, cessation of OAC was independently associated with the risk of stroke, adverse cardiovascular events and mortality. Bleeding events and some variables associated with higher bleeding risk are responsible for OAC cessation.
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Even though the Khorana risk score (KRS) has been validated to predict against the development of VTE among patients with cancer, it has a low positive predictive value. It is also unknown whether the score predicts outcomes in patients with cancer with established VTE. We selected a cohort of patients with active cancer from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the prognostic value of the KRS at inception in predicting the likelihood of VTE recurrences, major bleeding and mortality during the course of anticoagulant therapy. ⋯ The C-statistic was 0.53 (0.50-0.56) for recurrent VTE, 0.56 (95 %CI: 0.54-0.59) for major bleeding and 0.54 (95 %CI: 0.52-0.56) for death. In conclusion, most VTEs occur in patients with low or moderate risk scores. The KRS did not accurately predict VTE recurrence, major bleeding, or mortality among patients with cancer-associated thrombosis.