RESUMEN
BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly prescribed for the prevention and treatment of thrombosis. However, DOACs are associated with extensive interference in coagulation assays. Herein, we evaluate raw activated charcoal (AC) as an adsorbent material, to minimise DOAC-associated interferences in routine and specialised coagulation parameters on CS-series analysers (Sysmex, Kobe, Japan). METHODS: Commercial human-derived non-anticoagulated plasma materials, with or without increasing concentrations of anticoagulant, were assayed for routine and specialised coagulation parameters before and after treatment with AC. RESULTS: Treatment of non-anticoagulated plasma with raw AC had minimal impact on routine and specialised coagulation parameters available on the CS-series; however, clinically relevant prolongations of certain activated partial thromboplastin time (APTT)-based assays were observed after treatment. Furthermore, in apixaban- and rivaroxaban-containing plasma material, AC efficiently adsorbed therapeutic and supratherapeutic DOAC concentrations; and, treatment with raw AC resolved DOAC-associated interferences on all affected routine and specialised coagulation parameters. CONCLUSIONS: Overall, raw AC efficiently adsorbed apixaban and rivaroxaban from human-derived plasma, without significantly affecting the majority of underlying routine and specialised coagulation parameters available on CS-series analysers.
RESUMEN
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global healthcare crisis. While SARS-CoV-2-associated COVID-19 affects primarily the respiratory system, patients with COVID-19 frequently develop extrapulmonary manifestations. Notably, changes in the hematological system, including lymphocytopenia, neutrophilia and significant abnormalities of hemostatic markers, were observed early in the pandemic. Hematological manifestations have since been recognized as important parameters in the pathophysiology of SARS-CoV-2 and in the management of patients with COVID-19. In this narrative review, we summarize the state-of-the-art regarding the hematological and hemostatic abnormalities observed in patients with SARS-CoV-2-associated COVID-19, as well as the current understanding of the hematological system in the pathophysiology of acute and chronic SARS-CoV-2-associated COVID-19.
Asunto(s)
COVID-19 , Hemostáticos , Humanos , SARS-CoV-2 , PandemiasRESUMEN
BACKGROUND: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity. OBJECTIVES: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH. METHODS: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated. RESULTS: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours. CONCLUSION: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.
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Hemofilia A , Hemostáticos , Enfermedades de von Willebrand , Humanos , Factor VIII/uso terapéutico , Factor VIII/metabolismo , Factor de von Willebrand/metabolismo , Hemofilia A/diagnóstico , Hemofilia A/tratamiento farmacológico , Semivida , Sistema del Grupo Sanguíneo ABORESUMEN
The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
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Fibrinolíticos/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Anticuerpos de Dominio Único/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Fibrinolíticos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/epidemiología , Anticuerpos de Dominio Único/efectos adversos , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto Joven , Factor de von Willebrand/antagonistas & inhibidoresRESUMEN
BACKGROUND: Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations. OBJECTIVES: This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations. METHODS: Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th-95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. RESULTS: One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m2. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range. CONCLUSION: These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.
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Fibrilación Atrial/tratamiento farmacológico , Inhibidores del Factor Xa/sangre , Inhibidores del Factor Xa/uso terapéutico , Sobrepeso/complicaciones , Tromboembolia Venosa/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Fibrilación Atrial/complicaciones , Monitoreo de Drogas , Inhibidores del Factor Xa/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Estudios Prospectivos , Tromboembolia Venosa/complicaciones , Adulto JovenAsunto(s)
Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Enfermedades Asintomáticas/epidemiología , Catéteres de Permanencia/efectos adversos , Trombosis/etiología , Dispositivos de Acceso Vascular/efectos adversos , Adolescente , Adulto , Anticoagulantes/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Trombofilia/etiología , Trombosis/diagnóstico , Trombosis/tratamiento farmacológico , Trombosis/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.
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Proteína ADAMTS13/genética , Púrpura Trombocitopénica Trombótica/congénito , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Proteína ADAMTS13/deficiencia , Adulto , Preescolar , Factor VIII/uso terapéutico , Femenino , Humanos , Masculino , Mutación , Plasma , Embarazo , Premedicación/métodos , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/genética , Accidente Cerebrovascular/prevención & controlAsunto(s)
Anafilaxia/inducido químicamente , Anticuerpos Monoclonales/uso terapéutico , Factores Inmunológicos/efectos adversos , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Rituximab/efectos adversos , Proteína ADAMTS13/deficiencia , Proteína ADAMTS13/inmunología , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Persona de Mediana Edad , Rituximab/uso terapéuticoRESUMEN
Multiple myeloma (MM) is a malignant disorder characterized by clonal proliferation of plasma cells. Renal impairment is a common complication. Contrast-induced nephropathy (CIN) is a form of acute renal failure that can occur in the setting of IV contrast administration. It is more commonly seen in patients with pre-existing renal impairment. Patients with MM commonly require contrast enhanced procedures. The literature regarding the safety of IV contrast in this cohort is lacking. A retrospective review was carried out in a university hospital to identify the incidence of CIN in patients with MM and to look for associated risk factors. 94 patients and 165 procedures were included in the analysis. 10% of procedures resulted in CIN. 59% (10/17) of creatinines had normalized within one month of the procedure. The only factor found to be significant for the development of CIN was the timing of the procedure (<18mths verses >18mths post diagnosis of MM; p = 0.045). CIN appears to occur at an increased rate in patients with MM. However this may be an over-estimation given the common occurrence of renal impairment in this cohort and the close temporal relationship which often exists between systemic illness and contrast-enhanced procedures.
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Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Medios de Contraste/efectos adversos , Mieloma Múltiple/diagnóstico por imagen , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.
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Resistencia a la Proteína C Activada/etiología , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Mieloma Múltiple/complicaciones , Trombina/biosíntesis , Trombosis/etiología , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Quimioterapia , Humanos , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Estudios Prospectivos , Trombina/análisis , Trombofilia , Trombosis/prevención & control , Adulto JovenRESUMEN
The link between myeloma and thrombosis is well established. Monoclonal gammopathy of undetermined significance (MGUS) has also been associated with an increased risk of thrombosis. It was recently demonstrated that patients with myeloma display changes in thromboelastometry that may indicate a prothrombotic state. There is little data with regard to changes in thromboelastography in patients with myeloma or MGUS. The aim of this study was to investigate the differing coagulation profiles of patients of patients with myeloma and MGUS by means of conventional coagulation tests and thromboelastography. Blood was taken by direct venepuncture from patients with myeloma, MGUS and normal controls. Routine coagulation tests were performed in an accredited hospital laboratory. Thromboelastography (TEG(®)) was performed as per the manufacturer's protocol. Eight patients were recruited in each group. Patients with myeloma had a significantly lower mean haemoglobin level than patients with MGUS or normal controls (p < 0.001). Patients with myeloma had a significantly more prolonged mean prothrombin time than normal controls (p = 0.018) but not patients with MGUS. Patients with myeloma had significantly higher median D-dimer levels than normal controls (p = 0.025), as did patients with MGUS (p = 0.017). Patients with myeloma had a significantly higher mean factor VIII level than normal controls (p = 0.009) and there was a non-significant trend towards patients with MGUS having higher factor VIII levels than normal controls (p = 0.059). There was no significant difference in thromboelastographic parameters between the three groups. Patients with MGUS appear to have a distinct coagulation profile which is intermediate between patients with myeloma and normal controls.
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Coagulación Sanguínea , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Trombosis , Anciano , Pruebas de Coagulación Sanguínea/métodos , Diagnóstico Diferencial , Factor VIII/análisis , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Hemoglobinas/análisis , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Mieloma Múltiple/sangre , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Proyectos de Investigación , Tromboelastografía/métodos , Trombosis/sangre , Trombosis/etiología , Trombosis/prevención & controlAsunto(s)
Insuficiencia Cardíaca/etiología , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/diagnóstico , Inmunoglobulina A/sangre , Mieloma Múltiple/complicaciones , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Miocardio/patología , Enfermedad Aguda , Antineoplásicos/administración & dosificación , Cuidados Críticos/métodos , Resultado Fatal , Insuficiencia Cardíaca/complicaciones , Neoplasias Cardíacas/secundario , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Recurrencia , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/terapiaRESUMEN
Myeloma has a well-described association with venous thromboembolism (VTE). There are few dedicated studies investigating the incidence and risk factors. Many assessment scores have been suggested to estimate the risk of VTE in patients with cancer but these have been validated in solid organ tumors. The records of patients with myeloma attending a university hospital between January 2007 and December 2012 were reviewed to investigate the incidence of VTE and the associated risk factors. In all, 217 patients with a mean (standard deviation) age at diagnosis of 65 (12) years were included. Of 217 patients, 12% had an episode of VTE, 69% received at least 1 immunomodulatory agent, and 95% had low or intermediate risk of VTE according to the Khorana score. Venous thromboembolism was a frequent occurrence in this cohort. Patients had many risk factors for VTE but no one was predictive. As myeloma outcomes continue to improve, a dedicated prospective study is warranted to investigate the most appropriate thromboprophylaxis strategy.