RESUMO
Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.
Assuntos
Antitrombinas/uso terapêutico , Hemorragia/induzido quimicamente , Insuficiência Renal Crônica/fisiopatologia , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Antídotos/uso terapêutico , Antitrombinas/efeitos adversos , Antitrombinas/farmacocinética , Fibrilação Atrial/complicações , Estudos de Coortes , Dabigatrana/efeitos adversos , Dabigatrana/farmacocinética , Dabigatrana/uso terapêutico , Interações Medicamentosas , Monitoramento de Medicamentos , Taxa de Filtração Glomerular , Hemorragia/tratamento farmacológico , Humanos , Rim/fisiopatologia , Taxa de Depuração Metabólica , Estudos Observacionais como Assunto , Polimedicação , Guias de Prática Clínica como Assunto , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/farmacocinética , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacocinética , Rivaroxabana/uso terapêutico , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/uso terapêuticoRESUMO
Emicizumab is a bi-specific humanized monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the activation of FX by FIXa. Recent observations showed that emicizumab when added to pooled normal plasma (PNP), hemophilic plasma or PNP added with unfractionated heparin is able to interfere with coagulation assays. To further explore the mechanisms of assay interference we investigated the effect of emicizumab on global coagulation assays for the PNP added with two direct oral anticoagulants, apixaban or argatroban. Aliquots of PNP were added with purified apixaban or argatroban at a concentration of 500 ng/mL and emicizumab at concentrations ranging from 0 to 100 µg/mL. Plasma samples were then tested for the activated partial thromboplastin time (APTT) and for thrombin generation (the latter for the apixaban plasma only). Emicizumab at a 25-50 µg/mL shortened the APTT of the PNP with or without apixaban or argatroban. The extent of correction was greater for the apixaban or argatroban plasma and amounted to 35% or 42%, respectively. The parameters of thrombin generation (lag-time and time-to-peak) for the PNP supplemented with apixaban were shortened by 30% or 25%, respectively and the endogenous thrombin potential and the peak-thrombin were marginally affected. Emicizumab attenuates in vitro the anticoagulant activity of the PNP induced by apixaban or argatroban as documented by the correction of prolonged APTT and velocity of thrombin generation (i.e., lag-time and time-to-peak). Whether the above effects have any relevance in vivo is unknown.
Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Arginina/análogos & derivados , Ácidos Pipecólicos , Plasma , Pirazóis , Piridonas , Sulfonamidas , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/farmacologia , Arginina/farmacocinética , Arginina/farmacologia , Hemofilia A/sangue , Humanos , Tempo de Tromboplastina Parcial , Ácidos Pipecólicos/farmacocinética , Ácidos Pipecólicos/farmacologia , Plasma/química , Plasma/metabolismo , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaAssuntos
Anticorpos Antifosfolipídeos/efeitos adversos , Anticorpos Antifosfolipídeos/imunologia , Anticoagulantes/uso terapêutico , Rivaroxabana/uso terapêutico , Trombose/tratamento farmacológico , Trombose/etiologia , Vitamina K/antagonistas & inibidores , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Humanos , Recidiva , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Trombose/sangue , Trombose/diagnóstico , Resultado do TratamentoRESUMO
Rivaroxaban, which targets factor Xa and does not reduce proteins C/S, was chosen to treat a 6-year-old girl with homozygous protein S (PS) deficiency who developed skin necrosis while on warfarin. Owing to the lack of experience with rivaroxaban in children, the girl was started with 5 mg once-daily, which was gradually increased to 40 mg daily. The increasing dosage was driven by the need to avoid recurrence of skin necrosis. During dose-escalation, four pharmacokinetics assays were carried out measuring drug plasma concentrations and their effect on hemostatic parameters. We report the laboratory work-up, with special reference to parameters of thrombin-generation. Rivaroxaban concentrations by HPLC were correlated with those by the anti-factor Xa assay (r(2) = 0.92, p < 0.01), but there was an overestimation by HPLC. Thrombin-generation parameters, such as the area under the curve (referred to as ETP), peak-thrombin, and velocity-index, when measured after addition of thrombomodulin, showed unexpected changes: ETP decreased, but peak-thrombin and velocity-index increased. Similar patterns were obtained in a PS-depleted plasma and in plasma from patients with heterozygous PS deficiency, but not in plasma from controls. In conclusion, these preliminary results suggest that PS may be a determinant of velocity and peak-thrombin, but not of the total amount of thrombin generated.
Assuntos
Coagulação Sanguínea , Inibidores do Fator Xa/uso terapêutico , Deficiência de Proteína S/sangue , Deficiência de Proteína S/tratamento farmacológico , Rivaroxabana/uso terapêutico , Trombina/metabolismo , Criança , Inibidores do Fator Xa/administração & dosagem , Feminino , Homozigoto , Humanos , Deficiência de Proteína S/congênito , Deficiência de Proteína S/genética , Rivaroxabana/administração & dosagemRESUMO
INTRODUCTION: The increasing and widespread use of direct oral anticoagulants (DOACs) demands guidelines and experts' consensus for their rational and safe use, especially in certain situations for which there is no evidence-based consensus, such as the periprocedural setting. Rivaroxaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF) and for treatment and prevention of venous thromboembolism (VTE) in major orthopedic surgery. This article is addressed to all the clinicians involved in the periprocedural approach of patients treated with rivaroxaban, with the aim to give practical recommendations to improve patients' management during and after surgery. AREAS COVERED: This article is based on a consensus of specialists involved in anticoagulant treatment and in periprocedural setting, including experts in thrombosis, cardiologists, internists, clinical pathologists and anesthesiologists. The authors performed a review of the literature and expressed statements based on the results of the review as well as on personal experience. EXPERT OPINION: Rivaroxaban is a safe and effective drug that simplifies management of anticoagulation also in patients undergoing invasive procedures. However, periprocedural management could be challenging and physicians must carefully balance the risk of bleeding and the risk of thrombosis.
Assuntos
Inibidores do Fator Xa/uso terapêutico , Morfolinas/uso terapêutico , Tiofenos/uso terapêutico , Administração Oral , Hemorragia/prevenção & controle , Humanos , Período Perioperatório , Complicações Pós-Operatórias/prevenção & controle , Risco , Rivaroxabana , Procedimentos Cirúrgicos Operatórios , Tromboembolia/prevenção & controleRESUMO
We report a case of a 6-year-old girl with severe protein S deficiency due to a homozygous mutation and recurrent episodes of skin necrosis. She developed purpura fulminans at birth and a catheter-related venous thrombosis complicated by massive pulmonary embolism at the sixth day of life. Long-term oral anticoagulant therapy with a vitamin K-antagonist was started with a therapeutic range of the international normalized ratio of prothrombin time between 2.0 and 3.0. Unfortunately, this common range was not sufficient because recurrent episodes of warfarin-induced skin necrosis developed if the international normalized ratio was <4.0. Vitamin K antagonists decrease plasma level of vitamin K-dependent coagulation proteins, including the natural anticoagulant protein C. In our patient, the hypercoagulable state due to warfarin-induced reduction of protein C, other than severe protein S deficiency, outweighed the anticoagulant efficacy of the inhibition of procoagulant factors II, VII, IX, and X. The switch of anticoagulant therapy from warfarin to rivaroxaban, a direct inhibitor of activated factor X that does not inhibit other vitamin K-dependent proteins, resulted in the disappearance of skin necrosis at 1 year of follow-up. Rivaroxaban may be considered as a valid anticoagulant alternative in patients with severe inherited protein S deficiency and warfarin-induced skin necrosis.
Assuntos
Anticoagulantes/uso terapêutico , Inibidores do Fator Xa , Morfolinas/uso terapêutico , Deficiência de Proteína S/tratamento farmacológico , Índice de Gravidade de Doença , Tiofenos/uso terapêutico , Anticoagulantes/farmacologia , Criança , Feminino , Humanos , Morfolinas/farmacologia , Deficiência de Proteína S/sangue , Deficiência de Proteína S/diagnóstico , Rivaroxabana , Tiofenos/farmacologia , Resultado do TratamentoRESUMO
Chronic liver disease is characterized by a global hemostatic defect including platelet-vessel wall interaction (primary hemostasis), coagulation and fibrinolysis that may cause abnormalities of the relevant laboratory tests. The causal relationship between abnormal tests and bleeding has been widely accepted, despite the fact that abnormal tests are poorly associated with the timing and incidence of actual bleeding. In this article, we review recent evidence from the literature that disputes the above paradigm, and opens new venues for laboratory/clinical research and patient management in this field.
Assuntos
Hemorragia/fisiopatologia , Hemostasia/fisiologia , Cirrose Hepática/sangue , Hemorragia/etiologia , Humanos , Cirrose Hepática/complicaçõesRESUMO
The treatment of choice for acute venous thromboembolism is anticoagulant therapy with fast-acting drugs (unfractionated or low-molecular-weight heparin or fondaparinux) aimed at preventing thrombus extension, followed by extended prophylaxis with vitamin K antagonists aimed at preventing recurrence. Experience accumulated over the years has demonstrated that strict laboratory monitoring is required for unfractionated heparin and vitamin K antagonists, making use of these drugs problematic for patients and physicians and prompting researchers to develop new anticoagulants equally effective but without the requirement for laboratory monitoring. The results of clinical trials to date, albeit limited, suggest that these new drugs will probably keep their promise. However, the definitive answer will come subsequent to these clinical trials, when clinicians will start to use these drugs to treat patients in the real world. It is likely that some sort of laboratory monitoring will be required at least for selected categories of patients. Accordingly, clinical laboratories should still be prepared to monitor patients, although the numbers may hopefully decrease sharply in the next decade or so.