Assuntos
Síndromes Compartimentais/diagnóstico , Deficiência do Fator VII/complicações , Procedimentos Ortopédicos/métodos , Ortopedia/estatística & dados numéricos , Osteomielite/complicações , Coxa da Perna/patologia , Adolescente , Assistência ao Convalescente , Idoso de 80 Anos ou mais , Síndromes Compartimentais/cirurgia , Fator VII/administração & dosagem , Deficiência do Fator VII/sangue , Fasciotomia/métodos , Feminino , Hematoma/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Osteomielite/diagnóstico por imagem , Dor/etiologia , Coxa da Perna/cirurgia , Trombose/etiologia , Trombose/terapia , Resultado do Tratamento , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/patologia , Adulto JovemRESUMO
PURPOSE: To summarize and analyze the early treatment of multiple injuries combined with severe pelvic fractures, especially focus on the hemostasis methods for severe pelvic fractures, so as to improve the successful rate of rescue for the fatal hemorrhagic shock caused by pelvic fractures. METHODS: A retrospective analysis was conducted in 68 cases of multiple trauma combined with severe pelvic fractures in recent 10 years (from Jan. 2006 to Dec. 2015). There were 57 males and 11 females. Their age ranged from 19 to 75 years, averaging 42 years. Causes of injury included traffic accidents in 34 cases (2 cases of truck rolling), high falling injuries in 17 cases, crashing injuries in 15 cases, steel cable wound in 1 case, and seat belt traction injury in 1 case. There were 31 cases of head injury, 11 cases of chest injury, 56 cases of abdominal and pelvic injuries, and 37 cases of spinal and limb injuries. Therapeutic methods included early anti-shock measures, surgical hemostasis based on internal iliac artery devasculization for pelvic hemorrhage, and early treatment for combined organ damage and complications included embolization and repair of the liver, spleen and kidney, splenectomy, nephrectomy, intestinal resection, colostomy, bladder ostomy, and urethral repair, etc. Patients in this series received blood transfusion volume of 1200-10,000 mL, with an average volume of 2850 mL. Postoperative follow-up ranged from 6 months to 1.5 years. RESULTS: The average score of ISS in this series was 38.6 points. 49 cases were successfully treated and the total survival rate was 72.1%. Totally 19 patients died (average ISS score 42.4), including 6 cases of hemorrhagic shock, 8 cases of brain injury, 1 case of cardiac injury, 2 cases of pulmonary infection, 1 case of pulmonary embolism, and 1 case of multiple organ failure. Postoperative complications included 1 case of urethral stricture (after secondary repair), 1 case of sexual dysfunction (combined with urethral rupture), 1 case of lower limb amputation (femoral artery thrombosis), and 18 cases of consumptive coagulopathy. CONCLUSION: The early treatment of multiple injuries combined with severe pelvic fractures should focus on pelvic hemostasis. Massive bleeding-induced hemorrhagic shock is one of the main causes of poor prognosis. The technique of internal iliac artery devasculization including ligation and embolization can be used as an effective measure to stop or reduce bleeding. Consumptive coagulopathy is difficult to deal with, which should be detected and treated as soon as possible after surgical measures have been performed. The effect of using recombinant factor VII in treating consumptive coagulopathy is satisfactory.
Assuntos
Fraturas Ósseas/terapia , Traumatismo Múltiplo/terapia , Ossos Pélvicos/lesões , Adulto , Embolização Terapêutica/métodos , Fator VII/administração & dosagem , Feminino , Fraturas Ósseas/complicações , Hemostasia Cirúrgica , Humanos , Artéria Ilíaca/cirurgia , Escala de Gravidade do Ferimento , Ligadura , Masculino , Pessoa de Meia-Idade , Traumatismo Múltiplo/complicações , Prognóstico , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Choque Hemorrágico/etiologia , Choque Hemorrágico/prevenção & controle , Adulto JovemRESUMO
Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC.
Assuntos
Fator IX/administração & dosagem , Fator IX/uso terapêutico , Fator VII/administração & dosagem , Fator VII/uso terapêutico , Fator X/administração & dosagem , Fator X/uso terapêutico , Hemorragia/prevenção & controle , Protrombina/administração & dosagem , Protrombina/uso terapêutico , Tromboembolia/prevenção & controle , Vitamina K/antagonistas & inibidores , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Coeficiente Internacional Normatizado , Guias de Prática Clínica como Assunto , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVE: This phase 1 study evaluated the safety and tolerability of single intravitreous injections (IVIs) of ICON-1 (Iconic Therapeutics, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). ICON-1 is a modified factor VIIa protein linked with the Fc portion of a human immunoglobulin G1. The molecule binds tissue factor overexpressed on choroidal neovascularization (CNV) in AMD. PATIENTS AND METHODS: Open-label, interventional, dose-escalation trial in 18 patients with CNV due to AMD, with six patients per dose cohort. Patients received a single IVI of ICON-1 at baseline in one of three escalating doses: 60 µg, 150 µg, or 300 µg. Standard anti-vascular endothelial growth factor treatment was allowed at the investigator's discretion at least 2 weeks after the ICON-1 injection; patients were followed up to 24 weeks. Dose escalation was based on the absence of significant safety events. At each study visit, best-corrected visual acuity (BCVA), ophthalmic examination (intraocular pressure, slit-lamp, and dilated fundus examination), and ophthalmic imaging (color fundus photography, fluorescein angiography, and optical coherence tomography) assessments were performed. The systemic pharmacokinetics of ICON-1 and presence of anti-ICON-1 antibodies were also assessed. RESULTS: ICON-1 was safe and well-tolerated up to the highest dose administered, which was 300 µg. Commonly reported adverse events were considered related to the IVI procedure or to the underlying nAMD. No significant systemic levels of ICON-1 or anti-ICON-1 antibodies were detected. Preliminary evidence of biological activity (improved BCVA, reduced central retinal thickness, decreased CNV size, and leakage) was most evident with the 300 µg dose at 1 to 2 weeks after the single ICON-1 injection. CONCLUSION: Intravitreous administration of ICON-1 in single doses up to 300 µg in eyes with neovascular AMD was safe and well-tolerated. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:336-345.].
Assuntos
Fator VII/administração & dosagem , Imunoconjugados/administração & dosagem , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Acuidade VisualRESUMO
Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs. 1 day, P = 0·001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8·5 vs. 2-3, P = 0·013) for a longer RT duration (2 days vs. 1 day, P = 0·005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (ß = 0·352, P = 0·001) and RT duration (ß = 0·405, P = 0·018). Overall, a ≈20 µg/kg perioperative RT was efficacious in 95·5% of cases. The infusion should be repeated ≈8 times in high-risk subsets (i.e. patients with a history of major bleeding).
Assuntos
Deficiência do Fator VII/diagnóstico , Deficiência do Fator VII/cirurgia , Adolescente , Adulto , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Fator VII/administração & dosagem , Deficiência do Fator VII/epidemiologia , Feminino , Hemorragia/etiologia , Hemorragia/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Procedimentos Cirúrgicos Operatórios/métodos , Avaliação de Sintomas , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available. AREAS COVERED: We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed. EXPERT OPINION: The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.
Assuntos
Coagulantes/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Fatores de Coagulação Sanguínea/administração & dosagem , Fatores de Coagulação Sanguínea/efeitos adversos , Fatores de Coagulação Sanguínea/uso terapêutico , Coagulantes/administração & dosagem , Coagulantes/efeitos adversos , Fator IX/administração & dosagem , Fator IX/efeitos adversos , Fator IX/uso terapêutico , Fator VII/administração & dosagem , Fator VII/efeitos adversos , Fator VII/uso terapêutico , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Fator VIII/uso terapêutico , Humanos , Infusões Intravenosas , Trombose/induzido quimicamente , Trombose/epidemiologiaAssuntos
Autoantígenos/imunologia , Hemofilia A/imunologia , Hemorragia/imunologia , Mucosa Bucal/irrigação sanguínea , Colágenos não Fibrilares/imunologia , Idoso , Autoanticorpos/sangue , Transfusão de Sangue , Ciclofosfamida/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Fator VII/administração & dosagem , Hemorragia/terapia , Humanos , Masculino , Prednisolona/administração & dosagem , Colágeno Tipo XVIIRESUMO
The article deals with the safety and efficiency of recombinant activated factor VII (Coagil VII, Russia) and prothrombin complex concentrate (protromplex-600, Baxter Austria) in the neonatal and pediatric cardiac surgery. The study included 56 children aged from 7 days to 5.5 years underwent surgery with cardiopulmonary bypass for congenital heart defects repair. Clinical and laboratory evidences suggest that Coagil VII and protromplex-600 effective for bleeding stop. The drugs have no negative impact on hemodynamics. We did not identify allergic reactions and thrombosis associated with the introduction of drugs in the pen operative period.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Coagulantes/uso terapêutico , Fator IX/uso terapêutico , Fator VII/uso terapêutico , Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Cardiopatias Congênitas/cirurgia , Hemostasia Cirúrgica/métodos , Protrombina/uso terapêutico , Pré-Escolar , Coagulantes/administração & dosagem , Combinação de Medicamentos , Circulação Extracorpórea , Fator IX/administração & dosagem , Fator VII/administração & dosagem , Fator VIIa/administração & dosagem , Fator X/administração & dosagem , Cardiopatias Congênitas/sangue , Humanos , Lactente , Recém-Nascido , Protrombina/administração & dosagem , Resultado do TratamentoRESUMO
Haemophilic arthropathy is the most prevalent joint disorder in haemophilia. This disorder is characterized by chronic synovitis and progressive destruction of joint cartilage. We report a case of arthroscopic synovectomy to reduce bleeding frequency in haemophilic arthropathy of the knee. Patient was a 15 years old male with haemophilic arthropathy of the left knee. We performed an arthroscopic synovectomy under tightly regulated factor VIII replacement therapy. There were villous synovial hypertrophy at all part of the joint, multiple bone and cartilage defect, and also anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) deficiency found intraoperatively. After 6 month follow up, subjective complain and bleeding frequency decreased significantly. The visual analog scale improved from 5-6 to 1-2, and the International Knee Documentation Committee Score increased from 49 to 66. Bleeding frequency decreased from 4-8 times per month to less than 1 time per month. Arthroscopic synovectomy performed in this case could reduce the pain, decrease the frequency of bleeding, and improve patient's functional outcome.
Assuntos
Transfusão de Sangue/métodos , Fator VII/administração & dosagem , Hemartrose/etiologia , Hemofilia A/complicações , Articulação do Joelho , Adolescente , Artroscopia , Hemartrose/diagnóstico , Hemartrose/terapia , Humanos , Injeções Intravenosas , Masculino , Resultado do TratamentoRESUMO
Although new oral anticoagulants (NOACs) represent an advance in anticoagulant therapy over vitamin K antagonists (VKAs), they nevertheless have a low, but significant risk for bleeding complications. Reversal agents for VKAs, such as prothrombin complex concentrates (PCCs), are currently being evaluated in preclinical studies for NOAC reversal. This article reviews the preclinical data for the most extensively studied PCC for NOAC reversal, Beriplex, a 4-factor PCC. The results from the Beriplex studies are also compared with those obtained with other reversal agents, including different nonactivated PCCs, activated PCCs, and recombinant activated factor VII.
Assuntos
Anticoagulantes/efeitos adversos , Fator IX/uso terapêutico , Fator VII/uso terapêutico , Fator X/uso terapêutico , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Modelos Biológicos , Protrombina/uso terapêutico , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/química , Anticoagulantes/farmacologia , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antitrombinas/química , Antitrombinas/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Fator IX/administração & dosagem , Fator IX/farmacologia , Fator VII/administração & dosagem , Fator VII/farmacologia , Fator X/administração & dosagem , Fator X/farmacologia , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Hemorragia/induzido quimicamente , Hemostasia/efeitos dos fármacos , Hemostáticos/administração & dosagem , Hemostáticos/farmacologia , Humanos , Protrombina/administração & dosagem , Protrombina/farmacologiaRESUMO
INTRODUCTION: In vivo animal data have shown prothrombin complex concentrate (PCC) to be effective in preventing bleeding induced by excessive plasma levels of the direct thrombin inhibitor dabigatran. This animal model study was designed to determine the risk of thrombosis associated with administration of a PCC (Beriplex P/N) to reverse dabigatran-induced bleeding. MATERIALS AND METHODS: Anesthetized rabbits were treated with initial 0, 75, 200 or 450 µg kg(-1) dabigatran boluses followed by continuous infusions to maintain elevated plasma dabigatran levels. At 15 min after the start of dabigatran administration, PCC doses of 0, 50 or 300 IU kg(-1) were administered. Thereafter, coagulation in an arteriovenous (AV) shunt was evaluated and histopathologic examination for thrombotic changes performed. Venous thrombosis was also assessed in a modified Wessler model. RESULTS: At the suprapharmacologic dose of 300 IU kg(-1), PCC increased thrombus weight during AV shunting, but this effect could be prevented by dabigatran at all tested doses. AV shunt occlusion after PCC administration was delayed by 75 µg kg(-1) dabigatran and abolished by progressively higher dabigatran doses. High-dose treatment with 300 IU kg(-1) PCC resulted in histologically evident low-grade pulmonary thrombi; however, that effect could be blocked by dabigatran in a dose-dependent manner (p=0.034). In rabbits treated with high-dose PCC, dabigatran inhibited thrombus formation during venous stasis. PCC effectively reversed dabigatran-induced bleeding. CONCLUSIONS: In this animal study, thrombosis after PCC administration could be prevented in the presence of dabigatran. PCC reversed dabigatran-induced excessive bleeding while retaining protective anticoagulatory activity of dabigatran.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana , Fator IX/toxicidade , Fator VII/toxicidade , Fator X/toxicidade , Hemorragia/prevenção & controle , Hemostáticos/toxicidade , Protrombina/toxicidade , Trombose Venosa/induzido quimicamente , Animais , Testes de Coagulação Sanguínea , Modelos Animais de Doenças , Combinação de Medicamentos , Fator IX/administração & dosagem , Fator VII/administração & dosagem , Fator X/administração & dosagem , Feminino , Hemorragia/sangue , Hemorragia/induzido quimicamente , Hemostáticos/administração & dosagem , Protrombina/administração & dosagem , Coelhos , Medição de Risco , Fatores de Risco , Trombina/metabolismo , Fatores de Tempo , Trombose Venosa/sangue , Trombose Venosa/prevenção & controleAssuntos
Anticoagulantes/administração & dosagem , Fatores de Coagulação Sanguínea/administração & dosagem , Fator IX/administração & dosagem , Fator VII/administração & dosagem , Fator X/administração & dosagem , Morfolinas/administração & dosagem , Protrombina/administração & dosagem , Tiofenos/administração & dosagem , Combinação de Medicamentos , Feminino , Humanos , Masculino , RivaroxabanaRESUMO
Autophagy has an important role in tumor biology of hepatocellular carcinoma (HCC). Recent studies demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a G-protein-coupled receptor called protease-activated receptor 2 (PAR2) for tumor growth. The present study aimed to investigate the interactions of autophagy and the coagulation cascade in HCC. Seventy HCC patients who underwent curative liver resection were recruited. Immunohistochemical staining and western blotting were performed to determine TF, FVII, PAR2 and light chain 3 (LC3A/B) expressions in tumors and their contiguous normal regions. We found that the levels of autophagic marker LC3A/B-II and coagulation proteins (TF, FVII and PAR2) were inversely correlated in human HCC tissues. Treatments with TF, FVII or PAR2 agonist downregulated LC3A/B-II with an increased level of mTOR in Hep3B cells; in contrast, knockdown of TF, FVII or PAR2 increased LC3A/B. Furthermore, mTOR silencing restored the impaired expression of LC3A/B-II in TF-, FVII- or PAR2-treated Hep3B cells and activated autophagy. Last, as an in vivo correlate, we administered TF, FVII or PAR2 agonist in a NOD/severe combined immunodeficiency xenograft model and showed decreased LC3A/B protein levels in HepG2 tumors with treatments. Overall, our present study demonstrated that TF, FVII and PAR2 regulated autophagy mainly via mTOR signaling. The interaction of coagulation and autophagic pathways may provide potential targets for further therapeutic application in HCC.
Assuntos
Autofagia , Coagulação Sanguínea , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células , Fator VII/administração & dosagem , Fator VII/genética , Fator VII/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Oligopeptídeos/farmacologia , Interferência de RNA , Receptor PAR-2/agonistas , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Tromboplastina/administração & dosagem , Tromboplastina/genética , Tromboplastina/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Four-factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three-factor PCC, which contains little FVII, has a similar effect. METHODS AND RESULTS: We performed an open-label, single-center, parallel-group study comparing the effect of a three-factor PCC (Profilnine SD) with that of a four-factor PCC (Beriplex P/N) on the pharmacodynamics of rivaroxaban in 35 healthy volunteers. After receiving 4 days of rivaroxaban 20 mg twice daily to obtain supratherapeutic steady-state concentrations, volunteers were randomized to receive a single 50 IU kg(-1) bolus dose of four-factor PCC, three-factor PCC or saline 4 h after the morning dose of rivaroxaban on day 5, and the effects of these interventions on prothrombin time and thrombin generation were determined. Within 30 min, four-factor PCC reduced mean prothrombin time by 2.5-3.5 s, whereas three-factor PCC produced only a 0.6-1.0-s reduction. In contrast, three-factor PCC reversed rivaroxaban-induced changes in thrombin generation more than four-factor PCC. CONCLUSIONS: This study demonstrates the potential of both three-factor and four-factor PCCs to at least partially reverse the anticoagulant effects of rivaroxaban in healthy adults. The discrepant effects of the PCC preparations may reflect differences in the procoagulant components present in each.
Assuntos
Anticoagulantes/administração & dosagem , Fatores de Coagulação Sanguínea/administração & dosagem , Fator IX/administração & dosagem , Fator VII/administração & dosagem , Fator X/administração & dosagem , Morfolinas/administração & dosagem , Protrombina/administração & dosagem , Tiofenos/administração & dosagem , Adolescente , Adulto , Área Sob a Curva , Índice de Massa Corporal , Esquema de Medicação , Combinação de Medicamentos , Fator VII/uso terapêutico , Feminino , Voluntários Saudáveis , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Rivaroxabana , Trombina/química , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Inhibitor development in severe haemophilia A patients is currently the most serious complication of factor VIII (FVIII) treatment. Although continuous infusion (CI) of FVIII concentrate during surgical procedures in haemophilia A patients has been shown to be beneficial, some publications suggest that CI increases the risk of inhibitor generation. We conducted a prospective subgroup analysis to investigate if CI of the high-purity, pasteurized, plasma-derived FVIII concentrate Beriate(®) P during surgery increases the risk of inhibitor formation. MATERIALS AND METHODS: Patients with severe haemophilia A (FVIII:C <1%) were included if they presented with a negative history of previous inhibitors, had ≥ 50 exposure days, and had been scheduled for a planned surgical procedure. A bolus infusion (30-50 IU/kg body weight) of Beriate(®) P was administered intravenously and followed by CI at a rate of 3-4 IU/kg body weight/hour. Dose adjustments were subsequently made based on daily measurements of plasma FVIII activity. RESULTS: Five patients (aged 8-34 years) with severe haemophilia A were included. The surgical procedures ranged from teeth extraction to internal fixation of a fracture. There was no inhibitor generation with CI of Beriate(®) P in patients undergoing surgery, and we did not observe any complications due to re-bleeding or virus transmission. CONCLUSION: Beriate(®) P was efficacious, safe, and well tolerated during CI.
Assuntos
Fator VII/uso terapêutico , Hemofilia A/complicações , Hemofilia A/terapia , Administração Intravenosa , Adolescente , Adulto , Segurança do Sangue , Criança , Fator VII/administração & dosagem , Fator VII/antagonistas & inibidores , Feminino , Hemofilia A/cirurgia , Humanos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
Bleeding management in cardiac surgery could be a great challenge for the surgeon and a life-threatening moment for the patient. Despite the fact that recombinant activated factor VII is now widely accepted as a useful adjunct in the management of postcardiotomy coagulopathy, its use in the course of recent thromboembolic event is rarely described. We hereby present a case of rescue recombinant activated factor VII administration to manage a severe coagulation disorder during surgical pulmonary embolectomy performed under cardiopulmonary bypass.
Assuntos
Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Embolectomia/efeitos adversos , Fator VII/administração & dosagem , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Embolia Pulmonar/cirurgia , Coagulantes/administração & dosagem , Fator VII/genética , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/complicações , Proteínas Recombinantes/efeitos adversos , Resultado do TratamentoRESUMO
Avoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes.
Assuntos
Fator VII/genética , Fator VII/imunologia , Fator X/genética , Fator X/imunologia , Protrombina/genética , Protrombina/imunologia , Animais , Anticorpos/imunologia , Galinhas , Fator VII/administração & dosagem , Fator X/administração & dosagem , Feminino , Expressão Gênica , Humanos , Imunização , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Protrombina/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Transgenes , Globinas beta/genéticaRESUMO
BACKGROUND: Monitoring bypassing agent therapy and observing concordance with clinical hemostasis is crucial in vital hemorrhages and major surgeries in patients with hemophilia having inhibitor. OBJECTIVE: We aimed to investigate the value of the thrombin generation assay (TGA) and thromboelastography (TEG) for monitoring hemostasis in patients with hemophilia having inhibitor, during supplementation therapy with bypassing agents. PATIENTS AND METHODS: The study group consisted of 7 patients with hemophilia having factor VIII inhibitor. All patients were male. The median age of the participants was 10 years. Age range was 6 to 32 years. The median inhibitor level was 10 Bethesda units (BU), with a range of 5 to 32 BU. A total of 17 bleeding episodes were evaluated. Both TEG and TGA tests were assessed in addition to clinical responses. Assessments were made prior to bypass agent therapy such as recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) for bleeding episodes, during the first hour and 24 hours after either intervention in patients. RESULTS: No relation between clinical response and TGA or TEG parameters was found in patients. There was no difference between clinical responses after rFVIIa and aPCC treatments. However, after aPCC treatment, endogenous thrombin potential and peak thrombin levels and also TEG R, K, and alpha angle degrees were significantly higher. CONCLUSIONS: In conclusion, we found that the clinical effectiveness of bypass therapy in hemophilia cannot be assessed by TGA and TEG.
Assuntos
Fatores de Coagulação Sanguínea/administração & dosagem , Fator VIII/antagonistas & inibidores , Fator VII/administração & dosagem , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Trombina/análise , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Testes de Coagulação Sanguínea/métodos , Estudos de Casos e Controles , Criança , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Tromboelastografia/métodos , Trombina/metabolismo , Tempo de Trombina , Adulto JovemRESUMO
The overexpression of tissue factor (TF) observed in numerous cancer cells and clinical samples of human cancers makes TF an ideal target for cancer therapy. The purpose of this study is to develop a TF-targeting energized fusion protein hlFVII-LDP-AE, which is composed of a human Factor VII light chain (hlFVII) as the targeting domain conjugated to the cytotoxic antibiotic lidamycin (LDM, LDP-AE) as the effector domain. The potential efficacy of hlFVII-LDP-AE for cancer therapy was tested in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays and in vivo with a BALB/c nude mouse xenograft model of human liver cancer line HepG2. The inhibitory concentration (IC(50)) value of hlFVII-LDP-AE varied from 0.15 to 0.64 nM for the various human tumor lines. hlFVII-LDP-AE showed a tumor growth inhibition rate of 90.6% at the dose of 0.6 mg/kg in in vivo animal experiments. The mechanism through which hlFVII-LDP-AE inhibits tumor growth also was determined by Hoechst 33342 staining and Tdt-mediated dUTP nick-end labeling (TUNEL) assay. hlFVII-LDP-AE causes tumor cell death through inducing chromatin condensation and cleavage of genomic DNA. These findings suggest that the hlFVII-LDP-AE protocol is efficacious and tolerated in the mouse model of human liver cancer HepG2 and has clinical applicability for treating cancer patients.
Assuntos
Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/farmacocinética , Enedi-Inos/administração & dosagem , Enedi-Inos/farmacocinética , Fator VII/administração & dosagem , Fator VII/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Tromboplastina/metabolismo , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Feminino , Células Hep G2 , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: There are situations where a pharmacokinetic (PK) study may not be possible in children, especially in neonates and infants. Under these circumstances, one would like to extrapolate PK parameters from adults or older children to neonates and infants. Allometric scaling is a method which can be used for PK extrapolation from adults to children. OBJECTIVES: The objective of this study was to evaluate the predictive performance of an allometric model for the prediction of clearance of three coagulation factors in children from adult clearance. METHODS: Clearance values for three coagulation factors (rVIIa, rVIII and rIX) for adults and children were obtained from the literature. The allometric model was developed from adult data and then the model was used to predict clearance of the coagulation factors in individual child. The predicted clearance value was then compared with the observed clearance value in that child. RESULTS: The results of the study indicated that the CL of the three coagulation factors tested in this study could be predicted with accuracy (≤30% prediction error) in most of the children from the allometric model developed from adults. CONCLUSIONS: The study indicated that allometric scaling could be applied to predict the CL of coagulation factors in children from adults with accuracy. The predicted clearance can then be used to select a dose to initiate a clinical trial (pharmacokinetics, safety and efficacy) in children.