RESUMEN
Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration-time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration-time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week.
Asunto(s)
Factor VIII , Hemofilia A , Factor de von Willebrand , Humanos , Factor VIII/farmacocinética , Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Factor de von Willebrand/farmacocinética , Factor de von Willebrand/administración & dosificación , Modelos Biológicos , Adulto , Masculino , Adulto Joven , Cinética , Polietilenglicoles/farmacocinética , Polietilenglicoles/administración & dosificación , AdolescenteRESUMEN
BACKGROUND: Hemorrhage is a leading cause of preventable death in trauma, cardiac surgery, liver transplant, and childbirth. While emphasis on protocolization and ratio of blood product transfusion improves ability to treat hemorrhage rapidly, tools to facilitate understanding of the overall content of a specific transfusion strategy are lacking. Medical modeling can provide insights into where deficits in treatment could arise and key areas for clinical study. By using a transfusion model to gain insight into the aggregate content of massive transfusion protocols (MTPs), clinicians can optimize protocols and create opportunities for future studies of precision transfusion medicine in hemorrhage treatment. METHODS: The transfusion model describes the individual round and aggregate content provided by four rounds of MTP, illustrating that the total content of blood elements and coagulation factor changes over time, independent of the patient's condition. The configurable model calculates the aggregate hematocrit, platelet concentration, percent volume plasma, total grams and concentration of citrate, percent volume anticoagulant and additive solution, and concentration of clotting factors: fibrinogen, factor XIII, factor VIII, and von Willebrand factor, provided by the MTP strategy. RESULTS: Transfusion strategies based on a 1:1:1 or whole blood foundation provide between 13.7 and 17.2 L of blood products over four rounds. Content of strategies varies widely across all measurements based on base strategy and addition of concentrated sources of fibrinogen and other key clotting factors. DISCUSSION: Differences observed between modeled transfusion strategies provide key insights into potential opportunities to provide patients with precision transfusion strategy.
Asunto(s)
Transfusión Sanguínea , Fibrinógeno , Hemorragia , Humanos , Transfusión Sanguínea/métodos , Factor VIII/administración & dosificación , Factor XIII , Fibrinógeno/administración & dosificación , Fibrinógeno/análisis , Hematócrito , Hemorragia/terapia , Hemorragia/sangre , Factor de von Willebrand/administración & dosificaciónRESUMEN
BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).
Asunto(s)
Coagulantes , Factor VIII , Hemofilia A , Hemorragia , Humanos , Esquema de Medicación , Semivida , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/prevención & control , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/uso terapéutico , Quimioprevención , Factor VIII/administración & dosificación , Factor VIII/uso terapéutico , Coagulantes/administración & dosificación , Coagulantes/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
INTRODUCTION: Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma-derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. AIM: We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. METHODS: Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. RESULTS: in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05-.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. CONCLUSION: Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.
Asunto(s)
Factor VIII , Hemofilia A , Factor de von Willebrand , Animales , Modelos Animales de Enfermedad , Factor VIII/administración & dosificación , Factor VIII/inmunología , Factor VIII/aislamiento & purificación , Hemofilia A/terapia , Inmunoglobulina G/inmunología , Ratones , Proteínas Recombinantes/administración & dosificación , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/aislamiento & purificaciónRESUMEN
BACKGROUND: Patients with symptomatic von Willebrand disease (VWD) should be offered long-term prophylaxis (LTP) to prevent recurrent bleedings. Our objective was to evaluate the effectiveness and safety of Voncento®, a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), administrated in LTP. METHODS: We included patients from the OPALE study (May 2016 to April 2021), a French multicenter observational study following patients with inherited VWD, who received a Voncento® LTP during the study period. RESULTS: Among the 130 OPALE-study patients, 23 patients (12 women) received a LTP and were therefore included. The median (range) age was 16 (1-85) years; 16 patients were type 3, 1 was type 2A, 6 were type 2B. Before inclusion, 19 (83%) were under LTP and 4 (17%) received on-demand (OD) treatment. The indications for initiating prophylaxis in the overall population were joint bleeding (43%), ear, nose, and throat (ENT) bleeding including epistaxis or oral bleeding (39%), and recurrent muscle hematoma (22%). The medians (ranges) dose of Voncento® per infusion, frequency, and weekly dose were 45 (33-109) IU/kg, 2 infusions per week, and 96 (44-222) IU/kg/week, respectively. The median (range) annualized bleeding rate (ABR) was 0.8, 0.7 (0-3.5), and 0 (0-2.3) for type 2A, 2B, 3 patients, respectively. There was no difference regarding to the dose, frequency of infusion, or in terms of ABR in 9/19 patients who replaced previous concentrates with Voncento®. During the study period, no adverse event was reported. CONCLUSION: These results suggest that Voncento® is effective to prevent recurrent bleedings in patients symptomatic VWD.
Asunto(s)
Factor VIII , Hemorragia , Enfermedades de von Willebrand , Factor de von Willebrand , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Factor VIII/administración & dosificación , Femenino , Hemartrosis/tratamiento farmacológico , Hemorragia/prevención & control , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/administración & dosificaciónRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of a plasma-derived factor VIII concentrate containing von Willebrand Factor (pdVWF/FVIII) in standard clinical practice in von Willebrand Disease (VWD) patients. METHODS: A retrospective, multicentric, observational study of VWD patients treated with Fanhdi®, a pdVWF/FVIII concentrate, from January 2011 to December 2017 was conducted at 14 centers in Spain. Efficacy and safety were evaluated for acute bleeding episodes, for prevention of bleeding in surgeries, and for secondary long-term prophylaxis. RESULTS: Seventy-two eligible patients, type 1, 2, 3 VWD (25%/38.9%/36.1%) were treated for spontaneous and traumatic bleeding (140 episodes, n = 41 patients), to prevent surgical bleeding (69 episodes, n = 43 patients); and for secondary long-term prophylaxis (18 programs, n = 13 patients). Replacement therapy with pdVWF/FVIII showed an excellent to good clinical efficacy in 96.7% of the bleeding episodes, 100% during surgical procedures and 100% during prophylaxis. No adverse events (AEs), nor serious AEs related to the product were observed. CONCLUSIONS: Fanhdi® was effective, safe and well tolerated in the management of bleeding episodes, the prevention of bleeding during surgeries, and for secondary long-term prophylaxis in VWD patients.
Asunto(s)
Factor VIII/uso terapéutico , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemostáticos/uso terapéutico , Enfermedades de von Willebrand/complicaciones , Factor de von Willebrand/uso terapéutico , Adolescente , Adulto , Anciano , Pérdida de Sangre Quirúrgica/prevención & control , Niño , Combinación de Medicamentos , Factor VIII/administración & dosificación , Femenino , Hemostáticos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , España , Adulto Joven , Factor de von Willebrand/administración & dosificaciónRESUMEN
BACKGROUND: Coagulopathic bleeding is common during adult extracorporeal membrane oxygenation (ECMO), and acquired von Willebrand syndrome is a contributing factor. We compared ECMO patient blood samples that were treated in vitro with recombinant von Willebrand Factor concentrate and plasma-derived von Willebrand Factor concentrate. Our hypothesis was that recombinant von Willebrand Factor (vWF) would have greater efficacy in increasing vWF function. Secondarily, we hypothesized that recombinant vWF would have less impact on thrombin generation. METHODS: Thirty ECMO patients and 10 cardiac surgical controls were enrolled in the study. ECMO patient blood samples were treated in vitro with low- and high-dose recombinant vWFs and low- and high-dose plasma-derived vWFs. Whole blood ristocetin-induced platelet aggregation (RIPA), plasma ristocetin cofactor activity (RCo), and thrombin generation were compared between ECMO patient blood samples and control blood samples and between vWF-treated ECMO patient blood samples and nontreated samples. RESULTS: ECMO patient blood samples had severely reduced median RIPA compared to control samples 2 ohms (1-12 [25th-75th percentile]) vs 20 ohms (11-42) (P < .001). Treatment of ECMO patient blood samples with high-dose recombinant vWF significantly increased median RIPA to 10 ohms (2-15) (P < .001), while low-dose recombinant vWF and low- and high-dose plasma-derived vWFs did not significantly increase RIPA; 6 ohms (3-14), 4 ohms (1-13), and 6 ohms (2-10), respectively (P = .25, >.99, and >.99). Treatment with high-dose recombinant vWF and low- and high-dose plasma-derived vWFs significantly increased median plasma RCo to 4.7 international units (IU)/mL (3.7-5.9), 3.3 IU/mL (2.7-4.8), and 3.9 IU/mL (3.4-5.3), respectively, compared to controls 1.8 IU/mL (1.5-2.3) (all P < .001). Treatment with low- and high-dose plasma-derived vWFs significantly increased mean endogenous thrombin potential (6270.2 ± 2038.7 and 6313.1 ± 1913.3) compared to nontreated samples (5856.7 ± 1924.6) (P = .04 and .006), whereas treatment with low- and high-dose recombinant vWFs had no significant effect on mean endogenous thrombin potential (5776.1 ± 2087.3 and 5856.2 ± 1946.4) (P > .99 for both comparisons). CONCLUSIONS: In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF was superior to low-dose recombinant vWF and plasma-derived vWF in terms of improving RIPA. In addition, recombinant vWF treatment did not increase endogenous thrombin potential, which may reduce overall thrombotic risk if it used to treat acquired von Willebrand syndrome in ECMO patients.
Asunto(s)
Oxigenación por Membrana Extracorpórea/métodos , Factor VIII/administración & dosificación , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/terapia , Factor de von Willebrand/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Factor VIII/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasma , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangre , Resultado del Tratamiento , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: Hepatitis E virus (HEV) is the leading cause of acute hepatitis throughout the world. Increasing blood component transfusion-associated HEV infections highlight the need for reliable virus inactivation procedures for plasma derivatives from pooled plasma donations. STUDY DESIGN AND METHODS: An animal infection study was conducted to evaluate the efficiency of HEV inactivation by pasteurization during the manufacturing process of the von Willebrand Factor/Factor VIII (VWF/FVIII) concentrate Haemate P/Humate-P (CSL Behring, Marburg, Germany). For this purpose, groups of pigs were inoculated with stabilized VWF/FVIII intermediate spiked with HEV-positive liver homogenate and exposed to increasing incubation times of 0, 3, 6, and 10 h at 60°C. Animals were evaluated for virus replication over 27 days and in a subsequent trial over 92 days. RESULTS: Virus replication was detected in animals up to the 6-h pasteurization group. In contrast, pasteurization for 10 h did not reveal virus detection when the observation period was 27 days. In an additional experiment using the 10-h pasteurized material, two individuals started virus excretion and seroconverted when the observation period was extended to 92 days. Based on the total infection rate (2 of 12) of the animals inoculated with the sample pasteurized for 10 h, a virus reduction factor of at least 4.7 log10 is calculated. CONCLUSION: This study demonstrates that pasteurization at 60°C for 10 h of an HEV-positive plasma derivative leads to the effective reduction of infectivity, resulting in a VWF/FVIII product with an appropriate margin of safety for HEV.
Asunto(s)
Transfusión de Componentes Sanguíneos/efectos adversos , Factor VIII/administración & dosificación , Virus de la Hepatitis E/genética , Hepatitis E/etiología , Pasteurización/métodos , Factor de von Willebrand/administración & dosificación , Enfermedad Aguda , Animales , Bioensayo/métodos , Factor VIII/análisis , Femenino , Calefacción/efectos adversos , Hepatitis/epidemiología , Hepatitis/virología , Hepatitis E/prevención & control , Masculino , Modelos Animales , Seguridad , Porcinos , Factores de Tiempo , Inactivación de Virus , Replicación Viral/genética , Factor de von Willebrand/análisisRESUMEN
Conventional treatment of hemophilia A (HA) requires repetitive IV injection of coagulation factor VIII (FVIII). Subcutaneous administration of FVIII is inefficient because of binding to the extravascular matrix, in particular to phospholipids (PLs), and subsequent proteolysis. To overcome this, recombinant dimeric fragments of von Willebrand factor (VWF) containing the FVIII-stabilizing D3 domain were engineered. Two fragments, called VWF-12 and VWF-13, demonstrated high binding affinity to recombinant human FVIII (rhFVIII) and suppressed PL binding in a dose-dependent manner. High concentrations of VWF fragments did not interfere with the functional properties of full-length VWF in vitro. The HA mouse model was used to study the effects of VWF-12 or VWF-13 on the in vivo pharmacokinetics of rhFVIII, demonstrating (1) no significant impact on rhFVIII recovery or half-life after a single IV administration; (2) enhanced bioavailability (up to 18.5%) of rhFVIII after subcutaneous administration; and (3) slow absorption (peak concentration, 6 hours) and prolonged half-life (up to 2.5-fold) of rhFVIII after subcutaneous administration. Formation of anti-FVIII antibodies was not increased after administration of rhFVIII/VWF-12 subcutaneously compared with rhFVIII IV. A single subcutaneous dose of rhFVIII/VWF-12 provided protection in the HA tail-bleeding model for up to 24 hours. In summary, recombinant VWF fragments support FVIII delivery through the subcutaneous space into vascular circulation without interfering with VWF or FVIII function. Slow resorption and excretion of FVIII after subcutaneous administration highlight the potential application of VWF fragments for subcutaneous FVIII prophylaxis in HA.
Asunto(s)
Factor VIII/farmacocinética , Hemofilia A/tratamiento farmacológico , Factor de von Willebrand/farmacocinética , Animales , Disponibilidad Biológica , Factor VIII/administración & dosificación , Factor VIII/uso terapéutico , Semivida , Hemorragia/prevención & control , Infusiones Subcutáneas , Ratones , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/uso terapéuticoRESUMEN
BACKGROUND: In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento® (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD. MATERIALS AND METHODS: The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento® who underwent surgery. RESULTS: In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1-9), the pre-operative loading dose was 41 IU VWF:RCo kg-1 (range: 18-147), and the total dose was 63 (range: 18-594). During major surgeries, the number of infusions was 4 (range: 1-23), the pre-operative loading dose was 43 (range: 25-66) IU VWF: RCo kg-1, and the total dose was 155 (range: 40-575). The median FVIII:C levels ranged from 78 to 165 IU dL-1 during 5 days after minor surgeries and from 86 and 167 IU dL-1 during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL-1 and between 34 and 76 IU dL-1 after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as "excellent" or "good" in 99% of patients. No thrombotic events related to Voncento® were recorded. DISCUSSION: The present study suggests that Voncento® is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.
Asunto(s)
Factor VIII/uso terapéutico , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Combinación de Medicamentos , Factor VIII/administración & dosificación , Factor VIII/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Procedimientos Quirúrgicos Operativos , Trombosis/inducido químicamente , Resultado del Tratamiento , Adulto Joven , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/efectos adversosRESUMEN
Peripartum replacement of factor VIII and von Willebrand factor is not usually required in type 1 von Willebrand disease, as the levels of endogenous factors tend to increase to within the normal range as a physiological change of pregnancy. However, there is wide heterogeneity of genotypes and phenotypes associated with type 1 von Willebrand disease. Here, we describe the anesthetic management of a parturient with type 1C von Willebrand disease, a subtype characterized by decreased plasma von Willebrand factor survival.
Asunto(s)
Analgesia Epidural/métodos , Analgesia Obstétrica/métodos , Factor VIII/administración & dosificación , Complicaciones Hematológicas del Embarazo/fisiopatología , Enfermedades de von Willebrand/fisiopatología , Factor de von Willebrand/administración & dosificación , Adulto , Combinación de Medicamentos , Femenino , Humanos , Periodo Periparto , EmbarazoRESUMEN
von Willebrand disease (VWD) is the most common inherited bleeding disorder characterised by a quantitative or qualitative deficiency in von Willebrand factor (VWF). During invasive surgical procedures, patients with VWD require additional treatment to maintain haemostasis; however, due to the complexity of VWD, there is a lack of consensus on the optimal management. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)-containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries. This review provides an overview of the current evidence for the surgical management of patients with VWD and, summarises the optimal treatment approach during the perioperative period, and highlights key unanswered questions and the research needed to address the evidence gaps.
Asunto(s)
Atención Perioperativa , Enfermedades de von Willebrand/terapia , Biomarcadores , Coagulación Sanguínea , Toma de Decisiones Clínicas , Desamino Arginina Vasopresina/administración & dosificación , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Atención Perioperativa/métodos , Índice de Severidad de la Enfermedad , Tromboembolia/diagnóstico , Tromboembolia/etiología , Tromboembolia/prevención & control , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/etiología , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/genéticaRESUMEN
Complex regional pain syndrome (CRPS) is a regional neuropathic pain syndrome. Excruciating pain often interferes with patients' ability to function normally. Spinal cord stimulators (SCS) have been effective in treating pain along with signs of sympathetic overactivity in patients with CRPS. Implantation of SCS is a high-risk interventional procedure with the potential for serious bleeding and neurological consequences in the spine. Meticulous evaluation and careful optimization are needed in patients with bleeding disorders.
Asunto(s)
Síndromes de Dolor Regional Complejo/terapia , Estimulación de la Médula Espinal/métodos , Enfermedades de von Willebrand/complicaciones , Síndromes de Dolor Regional Complejo/etiología , Femenino , Fracturas Cerradas/cirugía , Humanos , Huesos Metatarsianos/lesiones , Persona de Mediana Edad , Factor de von Willebrand/administración & dosificaciónAsunto(s)
Hemostasis/fisiología , Enfermedades de von Willebrand/tratamiento farmacológico , Factor de von Willebrand/uso terapéutico , Anciano , Angiodisplasia/complicaciones , Angiodisplasia/fisiopatología , Desamino Arginina Vasopresina/uso terapéutico , Factor VIII/metabolismo , Femenino , Hemostáticos/uso terapéutico , Humanos , Infusiones Intravenosas/métodos , Persona de Mediana Edad , Pruebas de Función Plaquetaria/métodos , Resultado del Tratamiento , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/genética , Enfermedades de von Willebrand/fisiopatología , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND & AIM: Acetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury. METHODS: Wild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300â¯mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence. RESULTS: In wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24â¯h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48â¯h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48â¯h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbß3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice. CONCLUSION: These studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver. LAY SUMMARY: Patients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.
Asunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Plaquetas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado/metabolismo , Factor de von Willebrand/metabolismo , Acetaminofén/administración & dosificación , Analgésicos no Narcóticos/administración & dosificación , Animales , Coagulación Sanguínea/efectos de los fármacos , Humanos , Hígado/patología , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Necrosis , Agregación Plaquetaria/efectos de los fármacos , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/genética , Factor de von Willebrand/farmacocinéticaRESUMEN
In type 3 von Willebrand disease (VWD3), the most severe form with absent von Willebrand factor (VWF), the bleeding phenotype is variable. Platelet contribution to the hemostatic defect in VWD3 calls upon further studies. We investigated the contribution of platelets to in vitro thrombin generation (TG) and platelet procoagulant activity in VWD3. TG was assessed by calibrated automated thrombogram (CAT) in platelet-poor (PPP) and -rich plasma (PRP) from 9 patients before and in 6 patients also 30 min after receiving their regular VWF therapy. Responsiveness of PPP to FVIII and protein S was also investigated. TG data were compared with routine laboratory variables, rotational thromboelastometry (ROTEM) and platelet expression of P-selectin and phosphatidylserine in flow cytometry. Compared with healthy controls, TG was markedly decreased in VWD3 PPP (peak thrombin was 16% of normal median), but not in PRP (77% of normal median) (p = 0.002). Six out of nine patients (67%) were high responders in their platelet P-selectin, and 5/9 (56%) in phosphatidylserine expression. Replacement therapy improved TG in PPP, while in PRP TG only modestly increased or was unaffected. In PPP, FVIII levels associated with TG and in vitro FVIII-supplemented TG inclined up to threefold. Conversely, a FVIII inhibitory antibody reduced plasma TG in all, but especially in patients with remnant FVIII levels. Inhibition of protein S improved plasma TG, particularly at low FVIII levels. ROTEM failed to detect VWD3.In VWD3, TG is reduced in PPP and regulated by FVIII and protein S, but TG is close to normal in PRP. VWD3 platelets seem to compensate for the FVIII-associated reduction in TG by their exposure of P-selectin and phosphatidylserine.
Asunto(s)
Plaquetas/metabolismo , Trombina/metabolismo , Enfermedad de von Willebrand Tipo 3/metabolismo , Proteína ADAMTS13/genética , Proteína ADAMTS13/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores , Coagulación Sanguínea , Factor VIII , Femenino , Citometría de Flujo , Genotipo , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Activación Plaquetaria , Recuento de Plaquetas , Proteína S , Tromboelastografía , Adulto Joven , Enfermedad de von Willebrand Tipo 3/diagnóstico , Enfermedad de von Willebrand Tipo 3/etiología , Enfermedad de von Willebrand Tipo 3/terapia , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismoAsunto(s)
Procedimientos Quirúrgicos Cardíacos/métodos , Factor VIII/administración & dosificación , Cuidados Preoperatorios/métodos , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/cirugía , Factor de von Willebrand/administración & dosificación , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Factor VIII/metabolismo , Humanos , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/metabolismoRESUMEN
OBJECTIVES: To make recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support including future research directions. DATA SOURCES: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts. STUDY SELECTION: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support. DATA EXTRACTION/DATA SYNTHESIS: This white paper focuses on clinical understanding and limitations of current strategies to monitor anticoagulation. For each test of anticoagulation, limitations of current knowledge are addressed and future research directions suggested. CONCLUSIONS: No consensus on best practice for anticoagulation monitoring exists. Structured scientific evaluation to answer questions regarding anticoagulation monitoring and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patient receiving extracorporeal life support to a registry.
Asunto(s)
Oxigenación por Membrana Extracorpórea/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Niño , Oxigenación por Membrana Extracorpórea/métodos , Oxigenación por Membrana Extracorpórea/tendencias , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/farmacología , Hemorragia/prevención & control , Humanos , Trombosis/prevención & control , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/efectos adversos , Factor de von Willebrand/farmacologíaRESUMEN
Essentials Knowledge of the interplay between FVIII and VWF pharmacokinetics (PK) is lacking. We characterized the capacity-limited PK of FVIII and VWF. The PK model described the PK of FVIII and VWF over a broad range of rFVIII doses. High-dose rFVIII treatment can reduce the endogenous VWF levels. BACKGROUND: Understanding of the pharmacokinetics (PK) interplay between factor VIII (FVIII) and von Willebrand factor (VWF) following high-dose FVIII treatment is lacking. OBJECTIVES: To characterize the PK of recombinant FVIII (rFVIII), VWF, and the rFVIII:VWF complex in hemophilia A rats following intravenous administration of rFVIII using PK modeling. A second aim was to investigate the effect of high daily dosing and constant expression of rFVIII on VWF exposure using PK simulations. METHODS: We developed a population PK model based on the principles of target-mediated drug disposition modeling, using data on total rFVIII and VWF plasma concentrations, and the rFVIII:VWF complex luminescent oxygen channeling immunoassay signal in hemophilia A rats following intravenous administration of rFVIII (17.5, 100, 1000, and 5000 IU kg-1 ). Additionally, we evaluated the influence of high-dose rFVIII treatment on the exposure of VWF using PK simulations. RESULTS: The plasma concentration-time profiles of total rFVIII and VWF, and the luminescent oxygen channeling immunoassay signal-time profiles of the rFVIII:VWF complex were adequately described using a two-compartment quasi-steady-state target-mediated drug disposition model (Kss = 0.14 nmol L-1 ). The elimination half-life of the rFVIII:VWF complex was dependent on the unbound plasma concentration of rFVIII. Additionally, we showed that high-dose rFVIII treatment may significantly reduce the endogenous VWF levels. CONCLUSIONS: We developed a population-based PK model describing the time-course of total rFVIII, total VWF, and the rFVIII:VWF complex over a broad range of rFVIII doses in hemophilia A rats.
Asunto(s)
Factor VIII/farmacocinética , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Factor de von Willebrand/farmacocinética , Administración Intravenosa , Animales , Modelos Animales de Enfermedad , Factor VIII/administración & dosificación , Femenino , Humanos , Masculino , Modelos Biológicos , Dinámicas no Lineales , Ratas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacocinética , Factor de von Willebrand/administración & dosificación , Factor de von Willebrand/metabolismoRESUMEN
BACKGROUND: There is a lack of prospective clinical trials specifically designed to evaluate the benefits of prophylaxis with vWF/FVIII concentrates in patients with inherited von Willebrand disease (vWD). The aim of the study was to compare efficacy of secondary long-term prophylaxis (PRO) with vWF/FVIII in the prevention of bleeding episodes in severe vWD patients to standard of care (on-demand treatment; ODT). MATERIALS AND METHODS: In this 12-month, phase III, open-label study (PRO.WILL), vWD patients (aged ≥6 years) were randomised to PRO (n=9; 5 completed) or ODT (n=10; 7 completed) treatment with Fanhdi®/Alphanate® (Grifols) according to current licensing status for use in vWD. We assessed the proportion of patients who did not present any spontaneous bleeding episode, adverse events (AEs) or thrombotic events. RESULTS: All patients on ODT had vWD type 2 or 3 vs 70% of patients on PRO. All ODT patients experienced bleeds vs 60% on PRO. PRO patients showed fewer bleeds (n=32 vs n=172 [112 in the same patient, mostly mucosal]; p<0.0001) and lower risk of bleeding (relative attributable risk estimate: -0.667; 95% CI: -2.374, -0.107; p<0.001). Most frequent bleeds in ODT and PRO groups were, respectively, epistaxis (n=52 vs n=15) and gastrointestinal (n=13 [9 in the same patient] vs n=1). While most bleeds lasted one day under ODT (31/32), only epistaxis did so in PRO group (14/15). No AEs due to study medication were observed. DISCUSSION: Despite the small sample size and the heterogeneity of the study population, patients on vWF/FVIII prophylaxis showed a reduction in bleeding risk and rate compared to on-demand treatment.