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1.
Ther Adv Cardiovasc Dis ; 14: 1753944720924255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32449469

RESUMO

BACKGROUND: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. METHODS: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. RESULTS: A total of 63 patients [pediatric (n = 6), adult (n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. CONCLUSION: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.


Assuntos
Centros Médicos Acadêmicos , Anticoagulantes/efeitos adversos , Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fator VIIa/administração & dosagem , Hemorragia/prevenção & controle , Hemostáticos/administração & dosagem , Padrões de Prática Médica , Centros Médicos Acadêmicos/economia , Idoso , Procedimentos Cirúrgicos Cardíacos/economia , Criança , Pré-Escolar , Custos de Medicamentos , Cálculos da Dosagem de Medicamento , Revisão de Uso de Medicamentos , Fator VIIa/efeitos adversos , Fator VIIa/economia , Feminino , Hemorragia/induzido quimicamente , Hemorragia/economia , Hemostáticos/efeitos adversos , Hemostáticos/economia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Uso Off-Label , Padrões de Prática Médica/economia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/economia , Estudos Retrospectivos , Fatores de Risco , Tromboembolia/induzido quimicamente , Resultado do Tratamento
3.
Arterioscler Thromb Vasc Biol ; 40(5): 1275-1288, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32212848

RESUMO

OBJECTIVE: Recent studies showed that FVIIa (factor VIIa), upon binding to EPCR (endothelial cell protein C receptor), elicits endothelial barrier stabilization and anti-inflammatory effects via activation of PAR (protease-activated receptor)-1-mediated signaling. It is unknown whether FVIIa induces PAR1-dependent cytoprotective signaling through cleavage of PAR1 at the canonical site or a noncanonical site, similar to that of APC (activated protein C). Approach and Results: Mouse strains carrying homozygous R41Q (canonical site) or R46Q (noncanonical site) point mutations in PAR1 (QQ41-PAR1 and QQ46-PAR1 mice) were used to investigate in vivo mechanism of PAR1-dependent pharmacological beneficial effects of FVIIa. Administration of FVIIa reduced lipopolysaccharide-induced inflammation, barrier permeability, and VEGF (vascular endothelial cell growth factor)-induced barrier disruption in wild-type (WT) and QQ46-PAR1 mice but not in QQ41-PAR1 mice. In vitro signaling studies performed with brain endothelial cells isolated from WT, QQ41-PAR1, and QQ46-PAR1 mice showed that FVIIa activation of Akt (protein kinase B) in endothelial cells required R41 cleavage site in PAR1. Our studies showed that FVIIa cleaved endogenous PAR1 in endothelial cells, and FVIIa-cleaved PAR1 was readily internalized, unlike APC-cleaved PAR1 that remained on the cell surface. Additional studies showed that pretreatment of endothelial cells with FVIIa reduced subsequent thrombin-induced signaling. This process was dependent on ß-arrestin1. CONCLUSIONS: Our results indicate that in vivo pharmacological benefits of FVIIa in mice arise from PAR1-dependent biased signaling following the cleavage of PAR1 at the canonical R41 site. The mechanism of FVIIa-induced cytoprotective signaling is distinctly different from that of APC. Our data provide another layer of complexity of biased agonism of PAR1 and signaling diversity.


Assuntos
Anti-Inflamatórios/administração & dosagem , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fator VIIa/administração & dosagem , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Receptor PAR-1/metabolismo , Animais , Modelos Animais de Doenças , Endocitose , Células Endoteliais/metabolismo , Endotoxinas , Feminino , Homozigoto , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Transgênicos , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/metabolismo , Mutação Puntual , Receptor PAR-1/genética , Transdução de Sinais
4.
Mem Inst Oswaldo Cruz ; 115: e190364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130371

RESUMO

Oral transmission of Chagas disease has been increasing in Latin American countries. The present study aimed to investigate changes in hepatic function, coagulation factor levels and parasite load in human acute Chagas disease (ACD) secondary to oral Trypanosoma cruzi transmission. Clinical and epidemiological findings of 102 infected individuals attended in the State of Pará from October 2013 to February 2016 were included. The most common symptoms were fever (98%), asthenia (83.3%), face and limb edema (80.4%), headache (74.5%) and myalgia (72.5%). The hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of 30 ACD patients were higher compared with controls, and this increase was independent of the treatment with benznidazole. Moreover, ACD individuals had higher plasma levels of activated protein C and lower levels of factor VII of the coagulation cascade. Patients with the highest parasite load had also the most increased transaminase levels. Also, ALT and AST were associated moderately (r = 0.429) and strongly (r = 0.595) with parasite load respectively. In conclusion, the present study raises the possibility that a disturbance in coagulation and hepatic function may be linked to human ACD.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença de Chagas/fisiopatologia , Fator VIIa/análise , Fígado/fisiopatologia , Proteína C/análise , Doença Aguda , Adulto , Biomarcadores/sangue , Brasil/epidemiologia , Estudos de Casos e Controles , Doença de Chagas/sangue , Doença de Chagas/enzimologia , Doença de Chagas/transmissão , Feminino , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Estudos Prospectivos
5.
Biochim Biophys Acta Biomembr ; 1862(6): 183214, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081704

RESUMO

Structural data on membrane proteins in a lipid membrane environment is challenging to obtain but needed to provide information on the, often essential, protein-lipid interplay. A common experimental bottleneck in obtaining such data is providing samples in sufficient amounts and quality required for structural studies. We developed a new production protocol for the single-pass transmembrane protein (SPTMP) tissue factor (TF), exploiting the high expression level in E. coli inclusion bodies and subsequent refolding. This provided more than 5 mg of functional TF per liter bacterial culture. This is substantially more than what was obtained by the classical approaches for expressing TF in the membrane-anchored configuration. We optimized reconstitution into circularized nanodiscs enabling the formation of stable, TF loaded nanodiscs with different lipid compositions and with a limited material waste. The blood coagulation cascade is initiated by the complex formation between TF and Factor VIIa (FVIIa), and we probed this interaction by a functional assay and SPR measurements, which revealed similar activity and binding kinetics as TF produced by other protocols, demonstrating that high-yield production does not compromise TF function. Furthermore, the amounts of sample produced permitted initial small angle X-ray scattering studies providing the first structural information about TF and its binding to FVIIa in a lipid environment. This strategy possibly allows for probing the multicomponent complex TF:FVIIa together with its substrate Factor X on a lipid bilayer, but may also be relevant as a production strategy for other SPTMP for which structural information, in general, is limited.


Assuntos
Fator VIIa/metabolismo , Bicamadas Lipídicas/química , Complexos Multiproteicos/química , Dobramento de Proteína , Tromboplastina/química , Animais , Escherichia coli/citologia , Escherichia coli/metabolismo , Fator X/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Métodos , Nanoestruturas , Ligação Proteica , Tromboplastina/metabolismo
6.
Hematology ; 25(1): 17-25, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852380

RESUMO

Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP.Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency. Patients received their routine FVII product (30 IU/kg plasma-derived FVII [pdFVII] or 25 µg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 µg/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48 hr after administration. FVIIa activity was determined using a one-stage clotting assay. PD parameters were derived from thrombin generation testing, using the Nijmegen hemostasis assay.Results: rVIIa-FP showed improved PK compared to rFVIIa, with 2- to 3-fold longer t1/2 and 4- to 8-fold lower clearance. Analysis of PD data showed a sustained suppression of lag time below 4.5 min (upper limit of healthy people) for rVIIa-FP compared to rFVIIa. AUEC and ECmax were similar across the two dose groups of rVIIa-FP and rFVIIa.Discussion: rVIIa-FP was well tolerated in patients with congenital FVII deficiency, showed a longer half-life and lower clearance compared to rFVIIa, and lag time remaining within healthy ranges for ≥8 hr.Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.


Assuntos
Deficiência do Fator VII/tratamento farmacológico , Fator VIIa/uso terapêutico , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Deficiência do Fator VII/sangue , Fator VIIa/efeitos adversos , Fator VIIa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/sangue , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Albumina Sérica Humana/efeitos adversos , Albumina Sérica Humana/análise , Albumina Sérica Humana/farmacologia , Albumina Sérica Humana/uso terapêutico , Resultado do Tratamento , Adulto Jovem
7.
Eur J Haematol ; 104(1): 15-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31661175

RESUMO

Bleeding related to portal hypertension and coagulopathy is a common complication in patients with cirrhosis. Complications and management of bleeding is a significant source of healthcare cost and utilization, as well as morbidity and mortality. Due to the scarcity of evidence surrounding transfusion strategies and hemostatic interventions in patients with cirrhosis, there has been significant debate regarding the best practice. Emerging data suggest that evidence supporting transfusion of packed red blood cells to a hemoglobin threshold of 7-8 g/dL is strong. thrombopoietin (TPO) receptor agonists have shown promise in increasing platelet levels and reducing transfusions preprocedurally, although have not specifically been found to reduce bleeding risk. Data for viscoelastic testing (VET)-guided transfusions appear favorable for reducing blood transfusion requirements prior to minor procedures and during orthotopic liver transplantation. Hemostatic agents such as recombinant factor VIIa, prothrombin complex concentrates, and tranexamic acid have been examined but their role in cirrhotic patients is unclear. Other areas of growing interest include balanced ratio and whole blood transfusion. In the following manuscript, we summarize the most up to date evidence for threshold-guided, VET-guided, balanced-ratio, and whole blood transfusions as well as the use of hemostatic agents in cirrhotic patients to provide practice guidance to clinicians.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Transfusão de Eritrócitos , Fator VIIa/uso terapêutico , Hemorragia , Hipertensão Portal , Cirrose Hepática , Hemorragia/sangue , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/etiologia , Hipertensão Portal/terapia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/terapia , Guias de Prática Clínica como Assunto , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/sangue , Proteínas Recombinantes/uso terapêutico
8.
Haemophilia ; 25(6): 1020-1027, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31769912

RESUMO

INTRODUCTION: Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals. AIM: To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period. METHODS: It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire. RESULTS: Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump. CONCLUSION: This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa.


Assuntos
Sistemas de Liberação de Medicamentos/instrumentação , Fator VIIa/administração & dosagem , Adulto , Idoso , Automação , Fator VIIa/uso terapêutico , Humanos , Masculino , Enfermeiras e Enfermeiros/estatística & dados numéricos , Projetos Piloto , Período Pós-Operatório , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Inquéritos e Questionários
9.
Blood Coagul Fibrinolysis ; 30(8): 385-392, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738288

RESUMO

: The novel agent pd-FVIIa/FX is a 1 : 10 protein weight mixture of activated factor VII (FVIIa) and factor X (FX) derived from donated blood plasma. A phase III clinical trial of pd-FVIIa/FX revealed high efficacy for bleeding episodes in haemophilia patients with inhibitors. However, up to now, only one case of this new agent being used for surgery had been reported. The objective of this study is to evaluate the perioperative haemostatic efficacy and safety of pd-FVIIa/FX in haemophilia patients with inhibitors. We retrospectively reviewed 25 operation charts from 14 haemophilia patients with high-responding inhibitors using pd-FVIIa/FX during the perioperative period. Efficacy was evaluated by attending physicians and results divided into four groups (excellent, good, fair, and poor). The operation chart was provided by nine Japanese medical institutes with expertise in haemophilia management. Out of the total of 25 surgical procedures, 44% (11/25) were classified as major surgery and the remainders were minor surgeries. In all of the surgeries but one, rFVIIa and/or APCC were administered in combination or sequential method. In all cases except one, the haemostatic efficiency rate was judged as excellent or good by treating physicians for an overall efficacy rate of 96%. No thrombotic adverse effects were reported. This study's results suggest that both combination and sequential therapy of pd-FVIIa/FX and other bypassing agents are well tolerated and effective for the control of perioperative bleeding in haemophilia patients with high-responding inhibitors.


Assuntos
Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemostáticos/normas , Assistência Perioperatória/métodos , Adulto , Combinação de Medicamentos , Quimioterapia Combinada/efeitos adversos , Fator VIIa/efeitos adversos , Fator X/efeitos adversos , Hemofilia A/imunologia , Hemofilia B/imunologia , Hemorragia/prevenção & controle , Hemostáticos/efeitos adversos , Hemostáticos/uso terapêutico , Humanos , Masculino , Assistência Perioperatória/efeitos adversos , Estudos Retrospectivos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/métodos , Procedimentos Cirúrgicos Operatórios/normas , Trombose/induzido quimicamente , Resultado do Tratamento , Adulto Jovem
13.
Haemophilia ; 25(6): 911-918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31489759

RESUMO

The use of activated factor VII (FVIIa) for the treatment of bleeding events in haemophilia patients with inhibitors was first reported over 30 years ago. Since then clinical trials, registries, case series, real-world experience and an understanding of its mechanism of action have transformed what was originally a scientific curiosity into one of the major treatments for inhibitor patients, with innovative therapeutic regimens, dose optimization and individualized care now widely practiced. Given current understanding and use, it might be easy to forget the years of clinical research that led up to this point; in this review, we lay out changes based on broad eras of rFVIIa use. These eras cover the original uncertainty associated with dosing, efficacy and safety; the transformation of care ushered in with its widespread use; and the optimization and individualization of patient care and the importance of specialized support provided by haemophilia treatment centres. Today with the introduction of novel prophylactic agents such as emicizumab, we once again find ourselves dealing with the uncertainties of how best to utilize rFVIIa and newer investigational variants such as marzeptacog alfa and eptacog beta; we hope that the experiences of the past three decades will serve as a guide for this new era of care.


Assuntos
Fator VIIa/farmacologia , Hemofilia A/complicações , Hemofilia A/imunologia , Hemorragia/tratamento farmacológico , Fator VIIa/imunologia , Fator VIIa/uso terapêutico , Hemorragia/complicações , Hemorragia/prevenção & controle , Humanos , Incerteza
14.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S14-S18, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517711

RESUMO

: The development of inhibitors continues to be the most important complication in severe hemophilia A. The management of inhibitor patients revolves around two basic principles: eradication of the inhibitor and management and prevention of bleeding. In this paper, we review the prophylactic treatments carried out in the last two decades with the two available bypassing agents and the results of the clinical trials carried out with the new molecules under investigation or already licensed for the prevention of hemorrhagic episodes in hemophilia, like emicizumab.


Assuntos
Hemofilia A/terapia , Hemorragia/prevenção & controle , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Fator VIIa/uso terapêutico , Humanos , Proteínas Recombinantes/uso terapêutico
16.
Arterioscler Thromb Vasc Biol ; 39(10): 2038-2048, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31412737

RESUMO

OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.


Assuntos
Ductos Biliares/cirurgia , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/fisiopatologia , Fator VIIa/metabolismo , Fator X/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Coagulação Sanguínea/fisiologia , Transtornos da Coagulação Sanguínea/fisiopatologia , Testes de Coagulação Sanguínea , Células Cultivadas , Modelos Animais de Doenças , Hepatócitos/metabolismo , Humanos , Cinética , Ligadura/métodos , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilserinas/metabolismo , Distribuição Aleatória
18.
Am J Case Rep ; 20: 1022-1026, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31303639

RESUMO

BACKGROUND Massive tongue hemorrhage in patients with hemophilia is a medical emergency because it can lead to airway obstruction. However, managing bleeding in patients with inhibitors is more difficult than in patients without inhibitors. We report a case of life-threatening massive tongue and retropharyngeal hematoma in a patient with hemophilia A who had inhibitors. CASE REPORT The patient was a 71-year-old man with severe hemophilia A with high-responding inhibitors. He was admitted to our hospital with dysarthria and dysphagia secondary to a massive tongue hematoma. Although bypassing therapy was started immediately after admission, he rapidly developed an airway obstruction and cardiopulmonary arrest secondary to suffocation. Cardiopulmonary resuscitation and surgical cricothyrotomy were performed, which restored his pulse and breathing. On day 5 of hospitalization, he underwent tracheotomy under inhibitor-neutralizing therapy, and we began emicizumab on day 19 of hospitalization to prevent further bleeding events. He recovered and was transferred to another hospital for rehabilitation on day 64 of hospitalization. CONCLUSIONS Because tongue hematomas progress dramatically within a few days, prompt airway maintenance by tracheotomy under appropriate hemostatic therapy must be considered. Furthermore, emicizumab induction after primary hemostasis prevents further bleeding. We suggest that initiating emicizumab therapy is a good choice to prevent further bleeding after critical bleeding events if the patient has not received the drug previously.


Assuntos
Hematoma/etiologia , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemorragia/etiologia , Doenças da Língua/etiologia , Idoso , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator VIIa/uso terapêutico , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico , Espaço Retroperitoneal
19.
Thromb Haemost ; 119(9): 1419-1432, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31266079

RESUMO

The activation of protease-activated receptor (PAR)-2 by factor Xa (fXa) promotes the release of tissue factor-positive microvesicles (TF+MV), and contributes to proliferation in cancer cells. This study examined the ability of direct oral anticoagulants (DOACs), apixaban and rivaroxaban, to inhibit the release of TF+MV from two cell lines (MDA-MB-231 and AsPC-1) as well as cell proliferation.Activation of the cells with fXa (10 nM) enhanced the release of TF+MV but was suppressed in the presence of either DOAC. These MVs were found to contain fVIIa, but not fXa. Incubation of cell lines with apixaban (1.8 µM) but not rivaroxaban (1.8 µM), in the absence of fXa decreased the release of TF+MV below that of resting cells, in a PAR2-dependent manner. Furthermore, incubation with apixaban reduced the proliferation rate in both cells lines. Incubation of purified fVIIa with apixaban but not rivaroxaban resulted in complete inhibition of fVIIa proteolytic activity as measured using two fVIIa chromogenic substrates. Pre-incubation of the cells with an inhibitory anti-fVIIa antibody, with apixaban or the blocking of PAR2 suppressed the release of TF+MV to a comparable level, and reduced cell proliferation but the effect was not cumulative.This study has established that the activation of PAR2 by TF-fVIIa complex is the principal mediator in augmenting the release of TF+MV as well as cancer cell proliferation. Importantly, for the first time we have shown that apixaban selectively inhibits the proteolytic activity of fVIIa as well as the signalling arising from the TF-fVIIa complex.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Micropartículas Derivadas de Células/metabolismo , Inibidores do Fator Xa/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/farmacologia , Piridonas/farmacologia , Tromboplastina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fator VIIa/metabolismo , Feminino , Humanos , Receptor PAR-2/metabolismo , Rivaroxabana/farmacologia , Transdução de Sinais
20.
Blood Transfus ; 17(3): 223-228, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31246563

RESUMO

One of the most serious complications of the treatment of severe haemophilia A is the development of alloantibodies against exogenous factor VIII (FVIII). Inhibitors render factor replacement therapy ineffective, exposing patients to a remarkably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in newer haemostatic therapies that are not based on the replacement of the deficient FVIII. This review will focus on the most interesting among these innovative therapies, emicizumab, and will provide an update on its current stage of clinical development.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII , Fator VIIa/uso terapêutico , Hemofilia A , Isoanticorpos/sangue , Fator VIII/antagonistas & inibidores , Fator VIII/metabolismo , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Humanos , Proteínas Recombinantes/uso terapêutico
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