RESUMEN
BACKGROUND: Direct oral anticoagulants (DOACs) may cause falsely increased levels of antithrombin (AT) activity depending on the AT activity method and the specific target of the DOAC. Activated carbon (AC) has proven to remove DOAC interference on PT, aPTT and LA assays. We evaluate whether AC could be useful to resolve DOAC interference on AT assays. METHODS: Normal pooled plasma (NPP) was diluted to obtain AT activity of 25 %, 50 % and 75 % respectively. The diluted NPPs were spiked with DOACs (apixaban, edoxaban, dabigatran and rivaroxaban) in concentrations of respectively 100, 250 and 500 ng/ml. DOAC concentrations and AT activity were tested at baseline and after treatment with 20 mg/ml AC. AT activity was measured with a FXa-based method (HemosIL Liquid Antithrombin®, Werfen). RESULTS: All DOAC concentrations were below the limit of quantification (LoQ) after addition of AC. DOAC interference on AT activity testing was removed by adding AC, resulting in correctly diagnosing low levels of AT for all dilutions. The influence of DOACs on AT activity was directly correlated to the concentration of the DOAC. As expected, only the anti-FXa DOACs influenced the used assay. CONCLUSIONS: AC effectively removes anti-FXa DOAC interference on FXa-based AT assays.
Asunto(s)
Antitrombinas , Carbón Orgánico , Humanos , Antitrombinas/farmacología , Inhibidores del Factor Xa/farmacología , Inhibidores del Factor Xa/uso terapéutico , Anticoagulantes/uso terapéutico , Pruebas de Coagulación Sanguínea , Rivaroxabán , Administración OralRESUMEN
BACKGROUND AND AIMS: Absolute coronary flow can be measured by intracoronary continuous thermodilution of saline through a dedicated infusion catheter (RayFlow®). A saline infusion rate at 15-20 mL/min induces an immediate, steady-state, maximal microvascular vasodilation. The mechanism of this hyperemic response remains unclear. We aimed to test whether local hemolysis is a potential mechanism of saline-induced coronary hyperemia. METHODS: Twelve patients undergoing left and right catheterization were included. The left coronary artery and the coronary sinus were selectively cannulated. Absolute resting and hyperemic coronary flow were measured by continuous intracoronary thermodilution. Arterial and venous samples were collected from the coronary artery and the coronary sinus in five phases: baseline (BL); resting flow measurement (Rest, saline infusion at 10 mL/min); hyperemia (Hyperemia, saline infusion at 20 mL/min); post-hyperemia (Post-Hyperemia, 2 min after the cessation of saline infusion); and control phase (Control, during infusion of saline through the guide catheter at 30 mL/min). RESULTS: Hemolysis was visually detected only in the centrifugated venous blood samples collected during the Hyperemia phase. As compared to Rest, during Hyperemia both LDH (131.50 ± 21.89 U/dL [Rest] and 258.33 ± 57.40 U/dL [Hyperemia], p < 0.001) and plasma free hemoglobin (PFHb, 4.92 ± 3.82 mg/dL [Rest] and 108.42 ± 46.58 mg/dL [Hyperemia], p < 0.001) significantly increased in the coronary sinus. The percentage of hemolysis was significantly higher during the Hyperemia phase (0.04 ± 0.02% [Rest] vs 0.89 ± 0.34% [Hyperemia], p < 0.001). CONCLUSIONS: Saline-induced hyperemia through a dedicated intracoronary infusion catheter is associated with hemolysis. Vasodilatory compounds released locally, like ATP, are likely ultimately responsible for localized microvascular vasodilation.
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Hiperemia , Circulación Coronaria/fisiología , Vasos Coronarios , Hemólisis , Humanos , TermodiluciónAsunto(s)
Corazón Auxiliar/normas , Enfermedades de von Willebrand/terapia , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Direct oral anticoagulants (DOACs) affect laboratory coagulations tests. Activated carbon (AC) can be used for adsorption of DOACs during acute human intoxications. OBJECTIVES: This study evaluates whether AC can also be used to resolve DOAC interference on in vitro clotting tests (prothrombin time [PT], activated partial thromboplastin time [aPTT], and lupus anticoagulant [LA] assays). PATIENTS/METHODS: Interference on PT, aPTT, Liquid anti-FXa, DTI, and LA screening/confirmation (SCT and dRVVT) was determined by spiking citrated plasma from 5 adult controls with 0, 20, 40, 80, 120, or 160 mg/mL AC. DOAC concentrations, PT, and aPTT were compared before and after AC addition to citrated plasma from patients receiving DOACs (n = 29), low molecular weight heparin (n = 10), and coumarin (n = 10) therapy. Samples from 69 LA screened patients were compared before and after AC addition. RESULTS: A concentration of 20 mg/mL AC had the lowest interference and was selected for further experiments. After AC addition, all DOAC concentrations were below the limit of quantification in the 29 treated patients, except for 2 apixaban samples. AC removed DOAC interference on PT and aPTT but had no impact on results obtained during coumarin or low molecular weight heparin therapy. Of 15 LA samples with interference resulting from DOAC therapy, 14 samples became negative and 1 positive after AC addition. Interference from coumarin therapy was not resolved. All 19 LA negative samples remained negative. AC treatment of the negative pooled plasma was required to avoid false-negative LA results in 21 known LA-positive samples. CONCLUSIONS: AC selectively removes DOAC interference on PT, aPTT, and LA assays.
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Antitrombinas/sangre , Coagulación Sanguínea/efectos de los fármacos , Recolección de Muestras de Sangre/métodos , Carbón Orgánico/química , Inhibidor de Coagulación del Lupus/sangre , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Administración Oral , Adsorción , Antitrombinas/administración & dosificación , Biomarcadores/sangre , Humanos , Valor Predictivo de las Pruebas , Datos Preliminares , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Patients with von Willebrand disease (VWD) type 2A or acquired von Willebrand syndrome (aVWS) as a consequence of implantation of left ventricular assist devices (LVAD) are both characterized by a loss of von Willebrand factor (VWF) function. Loss of VWF function is however more severe in VWD type 2A than in LVAD patients. OBJECTIVES: To compare VWF function in patients with VWD type 2A and LVAD-induced aVWS to highlight the differences in VWF activity and to stress the importance of VWF multimer analysis for correct diagnosis of aVWS in LVAD patients. PATIENTS/METHODS: Plasma samples from nine VWD type 2A, nine LVAD patients, and 20 healthy donors (HD) were analyzed for VWF function (VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag) and loss of high molecular weight (HMW) VWF multimers. RESULTS: A severely impaired VWF function was indeed confirmed in all VWD 2A patients. HMW VWF multimers were severely reduced compared to HD (0% [0, 12.29] vs 34.19% [31.68, 38.88] for HD, P < 0.001) and this loss was reflected by VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios <0.7. In contrast, VWF function was less affected in LVAD patients. Although HMW VWF multimers were reduced in all patients (20.31% [15.84, 21.71], vs 34.19% [31.68, 38.88] for HD, P < 0.001), six out of nine LVAD patients had normal VWF:CB/VWF:Ag or VWF:RCo/VWF:Ag ratios (>0.7). CONCLUSIONS: VWF:CB/VWF:Ag or VWF:RCo/VWF:Ag analysis allows detection of impaired VWF function in VWD type 2A but not always in LVAD-induced aVWS patients. In contrast, VWF multimeric analysis allows detection of the loss of HMW VWF multimers in both groups of patients. Hence, performing VWF multimer analysis is crucial to detect aVWS in LVAD patients.
RESUMEN
BACKGROUND: Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti-factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients. STUDY DESIGN: Pharmacokinetic and pharmacodynamic study. SETTING & PARTICIPANTS: 18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7. RESULTS: Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072µg/L/h, mean maximum concentration was 172.6µg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2µg/L. LIMITATIONS: Higher rivaroxaban doses and patients with substantial residual kidney function were not studied. CONCLUSIONS: A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial.
Asunto(s)
Inhibidores del Factor Xa/administración & dosificación , Morfolinas/administración & dosificación , Diálisis Renal , Tiofenos/administración & dosificación , Administración Oral , Área Bajo la Curva , Fibrilación Atrial/complicaciones , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/sangre , Inhibidores del Factor Xa/farmacocinética , Inhibidores del Factor Xa/uso terapéutico , Femenino , Semivida , Hemorragia/inducido químicamente , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Morfolinas/efectos adversos , Morfolinas/sangre , Morfolinas/farmacocinética , Morfolinas/uso terapéutico , Rivaroxabán , Tiofenos/efectos adversos , Tiofenos/sangre , Tiofenos/farmacocinética , Tiofenos/uso terapéutico , Tromboembolia/prevención & control , Trombofilia/tratamiento farmacológico , Trombofilia/etiologíaRESUMEN
The Belgian national External Quality Assessment Scheme performed a nationwide survey using lyophilised plasma samples spiked with dabigatran or rivaroxaban to demonstrate to the Belgian clinical laboratories how these drugs affect their routine coagulation assays prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and antithrombin. Virtually all Belgian laboratories performing routine coagulation testing (189/192) participated in the survey. Both, dabigatran and rivaroxaban significantly prolonged the PT and aPTT in a concentration- and reagent-dependent manner. PT reagents were more influenced by rivaroxaban than by dabigatran and aPTT reagents more influenced by dabigatran than by rivaroxaban. Among PT reagents, Neoplastin R® was the most sensitive to rivaroxaban and Innovin® and Thromborel S® the least sensitive. Converting PT results to INR only increased the variability between reagents. Among aPTT reagents, Actin FSL® was the least sensitive to dabigatran while the other aPTT reagents showed slightly higher sensitivities. The presence of dabigatran led to falsely reduced fibrinogen concentrations when measured with a low thrombin concentration reagent. The presence of dabigatran caused an overestimation of the antithrombin level when measured with a thrombin-based activity assay and the presence of rivaroxaban an overestimation of the antithrombin level when measured with a FXa-based assay. Instrument-related differences were found for all tested parameters. In conclusion, this paper provides detailed information on the effect of dabigatran and rivaroxaban on routine coagulation assays as performed with a large number of reagent/instrument combinations.
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Anticoagulantes/administración & dosificación , Bencimidazoles/administración & dosificación , Coagulación Sanguínea/efectos de los fármacos , Ensayos de Aptitud de Laboratorios/métodos , Morfolinas/administración & dosificación , Tiempo de Tromboplastina Parcial/normas , Tiempo de Protrombina/normas , Tiofenos/administración & dosificación , beta-Alanina/análogos & derivados , Administración Oral , Antitrombinas/metabolismo , Bélgica , Biomarcadores/sangre , Dabigatrán , Relación Dosis-Respuesta a Droga , Diseño de Equipo , Fibrinógeno/metabolismo , Encuestas de Atención de la Salud , Humanos , Variaciones Dependientes del Observador , Tiempo de Tromboplastina Parcial/instrumentación , Valor Predictivo de las Pruebas , Tiempo de Protrombina/instrumentación , Indicadores de Calidad de la Atención de Salud/normas , Reproducibilidad de los Resultados , Rivaroxabán , Factores de Tiempo , beta-Alanina/administración & dosificaciónRESUMEN
OBJECTIVE: Platelet α2A-adrenergic receptors (ARs) mediate platelet aggregation in response to sympathetic stimulation. The 6.3-kb variant of α2A-AR gene is associated with increased epinephrine-induced platelet aggregation in healthy volunteers. The cytochrome P450 2C19*2 (CYP2C19*2) loss-of-function allele influences P2Y12-mediated platelet inhibition and hence the rate of major adverse cardiovascular events. We assessed the influence of 6.3-kb α2A-AR gene variant on platelet aggregation and its interaction with CYP2C19*2 loss-of-function allele in patients with stable angina on aspirin and clopidogrel (dual antiplatelet therapy). APPROACH AND RESULTS: Aggregation to 5 increasing doses of epinephrine (from 0.156 to 10 µmol/L) was assessed in aggregation units by Multiplate Analyzer and platelet reactivity in P2Y12 reactivity units and % inhibition by VerifyNow P2Y12 assay before percutaneous revascularization. Gene polymorphisms were analyzed with TaqMan Drug Metabolism assay. Of 141 patients, aggregation was higher in 6.3-kb carriers (n=52) when compared with wild types (n=89) at all epinephrine doses (P<0.05) apart from 10 µmol/L (P=0.077). Percentage inhibition was lower (P=0.048) in 6.3-kb α2A-AR carriers. Percentage inhibition was lower (P=0.005) and P2Y12 reactivity units was higher (P=0.012) in CYP2C19*2 allele carriers. Higher P2Y12 reactivity units (P=0.037) and lower percentage inhibition (P=0.009) were observed in carriers of both 6.3-kb α2A-AR variant and CYP2C19*2 allele when compared with wild-type or with either mutation on its own. CONCLUSIONS: The 6.3-kb α2A-AR variant is associated with increased platelet reactivity to epinephrine and has an additive effect along with CYP2C19*2 loss-of-function allele on P2Y12-mediated platelet responses in patients with stable angina on dual antiplatelet therapy.