RESUMO
Eptacog beta (activated), a recombinant human factor VIIa (rFVIIa), was approved by the US Food and Drug Administration (FDA) in 2020 (SEVENFACT®, LFB & HEMA Biologics) and the European Medicines Agency (EMA) in 2022 (CEVENFACTA®, LFB). In Europe, eptacog beta is indicated for the treatment of bleeds and the prevention of bleeds during surgery or invasive procedures in adults and adolescents (≥12 years old) with congenital haemophilia A or B with high-titre inhibitors (≥5 BU) or with low-titre inhibitors who are expected to have a high anamnestic response to factor VIII or factor IX, or to be refractory to increased dosing of these factors. The efficacy and safety of eptacog beta were evaluated in three Phase III clinical studies, PERSEPT 1, 2 and 3. For the EMA filing dossier, the analysis of data from PERSEPT 1 and 2 differed from the analysis used to support the filing in the US. In this review, we summarise current data regarding the mode of action, clinical efficacy and safety of eptacog beta for the management of haemophilia A and B in patients with inhibitors from a European perspective. In addition to providing a valuable summary of the analyses of the clinical data for eptacog beta conducted for the EMA, our review summarises the potential differentiators for eptacog beta compared with other current bypassing agents.
Assuntos
Fator VIIa , Hemofilia A , Adulto , Adolescente , Humanos , Criança , Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Emicizumab is used as a subcutaneous prophylaxis for prevention of bleeding episodes in patients with haemophilia A (HA) with and without inhibitors. While low bleeding rates were observed in clinical trials, patients still experience breakthrough bleeds (BTBs) with emicizumab in the real-world. Current guidelines recommend use of recombinant activated factor VII (rFVIIa) for treatment of BTBs in patients with inhibitors. Due to thrombotic events observed in the HAVEN 1 study, activated prothrombin complex concentrate (aPCC) should be used with caution. OBJECTIVES: The objective of this review is to identify and discuss real-world data on the frequency of BTBs and the safety of concomitant rFVIIa use in patients with inhibitors on emicizumab prophylaxis. METHODS: A search of the following databases was conducted on 15 July 2022: BIOSIS Previews® , Current Contents Search® , Embase® , MEDLINE® . Search terms included 'real world', 'haemophilia A', and 'emicizumab'. RESULTS AND CONCLUSIONS: Eleven relevant publications were identified (seven original research articles and four congress abstracts). The frequency of BTBs specifically for HA patients with inhibitors was described in three publications with 5%-56% patients on emicizumab reporting ≥1 bleeding episode. Treatment of these BTBs appeared to be managed according to relevant guidelines. Importantly, no thrombotic complications occurred during concomitant rFVIIa use. Due to the nature of real-world studies, direct comparison of the results between studies is limited. However, real-world data show that BTBs in inhibitor patients during emicizumab prophylaxis can be safely treated with rFVIIa.
Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Hemofilia A , Trombose , Humanos , Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Fator VIII/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Trombose/complicações , Proteínas RecombinantesRESUMO
OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs). DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Eleven references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. MEASUREMENTS AND MAIN RESULTS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One weak recommendation and three consensus statements are presented. CONCLUSIONS: Evidence supporting recommendations for administration of antifibrinolytics (EACA or tranexamic acid), rFVIIa, and THAs were sparse and inconclusive. Much work remains to determine effective and safe usage strategies.
Assuntos
Antifibrinolíticos , Técnica Delphi , Oxigenação por Membrana Extracorpórea , Hemostáticos , Ácido Tranexâmico , Humanos , Antifibrinolíticos/uso terapêutico , Antifibrinolíticos/administração & dosagem , Oxigenação por Membrana Extracorpórea/métodos , Criança , Hemostáticos/uso terapêutico , Hemostáticos/administração & dosagem , Ácido Tranexâmico/uso terapêutico , Ácido Tranexâmico/administração & dosagem , Fator VIIa/uso terapêutico , Fator VIIa/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Recém-Nascido , Ácido Aminocaproico/uso terapêutico , Ácido Aminocaproico/administração & dosagem , Hemorragia/prevenção & controle , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Lactente , ConsensoRESUMO
BACKGROUND: Bleeding after surgery on the thoracic aorta is a frequent complication, and can be associated with a significant increase in morbidity and mortality. Recombinant activated factor VII (rFVIIa) was developed initially for treating patients with hemophilia; however, it has been used increasingly "off-label" to achieve hemostasis after thoracic aortic procedures. OBJECTIVE: This scoping review aimed to present the available literature on the role of rFVIIa in the management of refractory postoperative bleeding after thoracic aortic surgery. METHODS/RESULTS: An electronic database search was conducted using Medline, Embase, Cochrane Library, and Google Scholar in June 2023. The authors included studies that reported the use of rFVIIa in patients undergoing surgical repair of ascending or descending aortic aneurysm or dissection. Single-case reports were excluded. Ten publications with a pooled number of 649 patients (319 patients received rFVIIa and 330 in the control groups) were identified: 3 case series, 6 retrospective studies, and 1 nonrandomized clinical trial. All studies reported the potential role of rFVIIa in correcting coagulopathy and reducing postoperative blood loss in this group of patients. Overall, there was not enough evidence to suggest that rFVIIa was associated with higher rates of thromboembolic complications or mortality. CONCLUSION: Limited evidence suggests that rFVIIa may be useful in managing postoperative refractory bleeding in patients undergoing thoracic aortic surgery. However, the impact of rFVIIa on thromboembolic complications and mortality rates remains unclear.
Assuntos
Fator VIIa , Hemorragia Pós-Operatória , Humanos , Fator VIIa/uso terapêutico , Hemorragia Pós-Operatória/etiologia , Proteínas Recombinantes/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study, we applied HES analysis to individual patient data from 4 randomized controlled trials evaluating rFVIIa (recombinant factor VIIa) 80 µg/kg to placebo. METHODS: We generated polychotomous strata of HES using absolute growth thresholds (≤0/<6/≥6 mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL), and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. RESULTS: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa-treated patients exhibited no hematoma expansion as compared with 25% of placebo (88/352)-treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa-(adjusted common odds ratio [acOR], 0.57 [95% CI, 0.43-0.75]). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR, 0.61 [95% CI, 0.47-0.80]). In both groups, mild-to-moderate expansion was observed in 38% to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR, 0.48 [95% CI, 0.30-0.76] versus <20 mL: acOR, 0.67 [95% CI, 0.47-0.95]; Pinteraction=0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR, 0.42 [95% CI, 0.19-0.91 versus >2 hours: acOR, 0.59 [95% CI, 0.44-0.79]; Pinteraction=0.30). CONCLUSIONS: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.
Assuntos
Hemorragia Cerebral , Fator VIIa , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator VIIa/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/induzido quimicamente , Proteínas Recombinantes , Hematoma/diagnóstico por imagem , Hematoma/tratamento farmacológicoRESUMO
BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.
Assuntos
Fator VIIa , Hemostáticos , Humanos , Fator VIIa/uso terapêutico , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/complicações , Hematoma/diagnóstico por imagem , Hematoma/tratamento farmacológico , Tomografia Computadorizada por Raios X , Hemostáticos/uso terapêuticoRESUMO
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.
Assuntos
Hemofilia A , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Fatores de Coagulação Sanguínea/uso terapêutico , Estudos Retrospectivos , Hemorragia/etiologia , Fator VIIa/uso terapêutico , Fator IX/uso terapêuticoRESUMO
INTRODUCTION: Haemophilia B patients with factor IX inhibitors have particularly unmet needs for conventional therapy. AIM: Phase II/III clinical trial, multicentre, open-label, prospective, self-controlled study was conducted to assess MC710 prophylaxis in haemophilia B patients with inhibitors. METHODS: We enrolled haemophilia patients who had received episodic or prophylactic treatment with bypassing agents up to that time. The participants continued their conventional therapy for 24 weeks and then MC710 was prophylactically infused intravenously every 2 or 3 days at 60 to 120 µg as FVIIa per kilogram of body weight for 24 weeks. The primary endpoint was the annual bleeding rate (ABR) requiring bypassing agents, which was compared intraindividually between the conventional therapy period and the MC710 prophylaxis period. RESULTS: A total of 11 male haemophilia B patients were enrolled. The median ABR ratio for each participant (the prophylaxis period ABR divided by the conventional therapy period ABR) was .33 (2.1/6.5), range from .00 to 3.77. ABR ratios for 9 of the 11 patients ranged from .00 to .60, and 3 of the 9 patients had zero bleeding events during the prophylaxis period. Meanwhile, ABR ratios for the remaining two patients were 2.53 and 3.77, respectively. Although a fibrinogen decrease recovered by the dose reduction was reported for only one participant as the sole adverse drug reaction in this study, no thrombotic events or other safety concerns were reported. CONCLUSION: MC710 prophylaxis is considered to be decrease the bleeding rate in haemophilia B patients with inhibitors without safety concerns.
Assuntos
Hemofilia A , Hemofilia B , Humanos , Masculino , Fator X/uso terapêutico , Fator X/farmacologia , Hemofilia B/complicações , Hemofilia B/tratamento farmacológico , Fator VIIa/uso terapêutico , Fator VIIa/farmacologia , Estudos Prospectivos , Hemorragia/prevenção & controle , Hemorragia/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêuticoRESUMO
OBJECTIVE: Aim: The authors evaluated the effectiveness of treatment with recombinant human coagulation factor VIIa and concentrate of all prothrombin complex factors in patients with massive postoperative bleeding that could not be controlled with traditional therapy. PATIENTS AND METHODS: Materials and Methods: In the period from 2020 to 2021, recombinant human coagulation factor VIIa was administered to 18 patients after cardiac surgery (group I), while the concentrate of all prothrombin complex factors was administered to 16 patients postoperatively (group II). During this period, 647 patients were operated on. The patients had normal coagulation screening tests (APTT, INR, TT, fibrinogen level, and PLT level) before surgery. Mean blood loss before and after administration of eptacog alfa and the total prothrombin complex concentrate was assessed. The mean dose of eptacog alfa was 30.95 mcg/kg b.w., and the total prothrombin complex factor concentrate dose was 14.17 mcg/kg b.w. After transfusion with red blood cell concentrate, fresh frozen plasma, and platelet concentrate, in the absence of improvement in the dynamics of postoperative drainage, it was decided to include recombinant human coagulation factor VIIa or a concentrate of all prothrombin complex factors in the treatment. RESULTS: Results: After administration of recombinant human coagulation factor VIIa at a dose of 30.95 mcg/kg b.w., bleeding stopped in 12 patients, but the remaining 6 patients required reoperation due to persistently high drainage. The decision to perform a rethoracotomy was made by a team of cardiothoracic surgeons and anesthesiologists, taking into account the dynamics of drainage (bleeding) and the hemodynamic stability of the patient. After the administration of concentrate of all prothrombin complex factors at a dose of 14.17 U/kg b.w., bleeding stopped in 12 patients. Four patients required reoperation due to persistent bleeding. CONCLUSION: Conclusions: Treatment with recombinant human coagulation factor VIIa and concentrate of all prothrombin complex factors is effective and safe for cardiac surgery patients.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Fator VIIa , Humanos , Fator VIIa/uso terapêutico , Fator VIIa/efeitos adversos , Protrombina/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Hemorragia/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversosRESUMO
Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator VIII/uso terapêutico , Terapia Genética , Hemofilia A/terapia , Hemofilia B/terapia , Anticorpos Neutralizantes , Fator IX/uso terapêutico , Fator VIIa/uso terapêutico , Meia-Vida , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Injeções Subcutâneas , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Albumina Sérica/uso terapêutico , Fator de von Willebrand/metabolismoRESUMO
We recently showed that clotting factor VIIa (FVIIa) binding to endothelial cell protein C receptor (EPCR) induces anti-inflammatory signaling and protects vascular barrier integrity. Inflammation and vascular permeability are thought to be major contributors to the development of hemophilic arthropathy following hemarthrosis. The present study was designed to investigate the potential influence of FVIIa interaction with EPCR in the pathogenesis of hemophilic arthropathy and its treatment with recombinant FVIIa (rFVIIa). For this, we first generated hemophilia A (FVIII-/-) mice lacking EPCR (EPCR-/-FVIII-/-) or overexpressing EPCR (EPCR++ FVIII-/-). Joint bleeding was induced in FVIII-/-, EPCR-/-FVIII-/-, and EPCR++FVIII-/- mice by needle puncture injury. Hemophilic synovitis was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections. EPCR deficiency in FVIII-/- mice significantly reduced the severity of hemophilic synovitis. EPCR deficiency attenuated the elaboration of interleukin-6, infiltration of macrophages, and neoangiogenesis in the synovium following hemarthrosis. A single dose of rFVIIa was sufficient to fully prevent the development of milder hemophilic synovitis in EPCR-/-FVIII-/- mice. The development of hemophilic arthropathy in EPCR-overexpressing FVIII-/- mice did not significantly differ from that of FVIII-/- mice, and 3 doses of rFVIIa partly protected against hemophilic synovitis in these mice. Consistent with the data that EPCR deficiency protects against developing hemophilic arthropathy, administration of a single dose of EPCR-blocking monoclonal antibodies markedly reduced hemophilic synovitis in FVIII-/- mice subjected to joint bleeding. The present data indicate that EPCR could be an attractive new target to prevent joint damage in hemophilia patients.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Receptor de Proteína C Endotelial/deficiência , Hemartrose/prevenção & controle , Hemofilia A/complicações , Animais , Anticorpos Monoclonais/farmacologia , Citocinas/fisiologia , Receptor de Proteína C Endotelial/antagonistas & inibidores , Receptor de Proteína C Endotelial/imunologia , Receptor de Proteína C Endotelial/fisiologia , Fator VIIa/uso terapêutico , Hemartrose/tratamento farmacológico , Hemartrose/etiologia , Hemartrose/fisiopatologia , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Camundongos , Camundongos Knockout , Punções/efeitos adversos , Ratos , Proteínas Recombinantes/uso terapêutico , Sinovite/etiologia , Sinovite/prevenção & controleRESUMO
Bleeding following cardiac surgery that warrants transfusion of blood products is associated with significant complications, including increased mortality at 1 year following surgery. Factor concentrates, such as prothrombin complex concentrate (PCC), or recombinant activated factor VII (rFVIIa) have been used off-label for bleeding in cardiac surgery that is refractory to conventional therapy. The objective of this retrospective study is to assess the hemostatic effectiveness of 4-factor PCC or rFVIIa for bleeding after a broad range of cardiac surgeries. Patients were included if they were at least 18 years of age and had undergone cardiac surgery with bleeding requiring intervention with 4-factor PCC or rFVIIa. There were no differences observed in the number of packed red blood cells (4-factor PCC: 2 units vs. rFVIIa: 2 units), fresh frozen plasma (0 units vs. 1 unit) or platelet (2 units vs. 2 units) transfusions following the administration of 4-factor PCC or rFVIIa. The patients in the rFVIIa group, required more cryoprecipitate than those in the 4-factor PCC group (4-factor PCC: 2 units (range 0-6) vs. rFVIIa: 2 units (range 0-8), p = 0.03). There were no differences in secondary outcomes of chest tube output at 2, 6, 12 and 24 hours, nor was there a difference in reexploration rates or the median length of stay in the intensive care unit. Thromboembolic complications at 30 days were similar between the two groups (4-factor PCC: 13% vs. rFVIIa 26%, p = 0.08). The total median dose requirement for 4-factor PCC was 1000 units (15 units/kg) and 2 mg (20 mcg/kg) for rFVIIa. The results demonstrate feasibility of utilizing the minimum amount of drug in order to achieve a desired effect. Both 4-factor PCC and rFVIIa appear to be safe and effective options for the management of bleeding associated with cardiac surgery.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Procedimentos Cirúrgicos Cardíacos , Fator VIIa , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Fator VIIa/uso terapêutico , Humanos , Estudos RetrospectivosRESUMO
Tissue factor (TF), an initiator of extrinsic coagulation pathway, is positively correlated with venous thromboembolism (VTE) of tumor patients. Beyond thrombosis, TF plays a vital role in tumor progression. TF is highly expressed in cancer tissues and circulating tumor cell (CTC), and activates factor VIIa (FVIIa), which increases tumor cells proliferation, angiogenesis, epithelial-mesenchymal transition (EMT) and cancer stem cells(CSCs) activity. Furthermore, TF and TF-positive microvesicles (TF+MVs) activate the coagulation system to promote the clots formation with non-tumor cell components (e.g., platelets, leukocytes, fibrin), which makes tumor cells adhere to clots to form CTC clusters. Then, tumor cells utilize clots to cause its reducing fluid shear stress (FSS), anoikis resistance, immune escape, adhesion, extravasation and colonization. Herein, we review in detail that how TF signaling promotes tumor metastasis, and how TF-targeted therapeutic strategies are being in the preclinical and clinical trials.
Assuntos
Micropartículas Derivadas de Células , Neoplasias , Trombose , Biologia , Coagulação Sanguínea , Micropartículas Derivadas de Células/metabolismo , Fator VIIa/uso terapêutico , Humanos , Tromboplastina/metabolismo , Trombose/tratamento farmacológicoRESUMO
To investigate the current experience and expertise for haemophilia inhibitor patient management in haemophilia treatment centres (HTCs) in mainland China. Questionnaires were distributed to 'tertiary tier A' hospital HTCs across China to collect information on treatment preferences for bleeding control, prophylaxis and inhibitor eradication, as well as their regimens in real-world clinical practice. Of 40 questionnaires distributed, 39 were returned. In all, 38 were analysable for treatment preferences and 34 for actual clinical practice. For haemostatic treatment, 76·3% (29/38) HTCs preferred activated recombinant human Factor VII (rFVIIa). In clinical practice, the most widely used by-pass agent was prothrombin complex concentrate (26 HTCs). Although 65·8% (25/38) of HTCs believed prophylaxis treatment was necessary, it was prescribed in only 12. Similarly, 65·8% (25/38) of HTCs believed immune tolerance induction (ITI) therapy was necessary but only 14·8% (92/622) of patients in 19 HTCs received low-dose ITI treatment. HTCs in relatively economically developed cities (with higher-than-average per-capita gross domestic product) had better access to haemostatic treatment, coagulation testing and were more likely to provide prophylaxis and ITI in practice. The present survey showed there were gaps in haemophilia inhibitor care between the HTC physicians' preferences and their actual clinical practice. More specific care guidelines, education and clinical decision support tools are needed to guide clinical practice.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemostáticos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Fator VIIa/uso terapêutico , Hemofilia A/sangue , Hemofilia A/epidemiologia , Hemofilia B/sangue , Hemofilia B/epidemiologia , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemorragia/epidemiologia , Humanos , Lactente , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Adulto JovemRESUMO
The development of alloantibodies (inhibitors) against coagulation factor VIII (FVIII) is the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA). We carried out a nationwide study focussing on patients with HA with inhibitors in China to evaluate the condition and management of this population. The study retrospectively analysed patient characteristics, clinical history, manifestation, treatment strategy as well as individual haemophilia care of 493 patients with inhibitors (466 with severe HA and 27 with non-severe HA) registered all over China. The median (interquartile range) age at diagnosis of FVIII inhibitors was 13 (5-28) years in patients with severe HA and 24 (10·5-39·5) years in patients with non-severe HA. Most patients (85%) had high-titre inhibitors. Prothrombin complex concentrate and recombinant activated coagulation factor VII were used respectively in 76·2% and 29·2% of patients for acute bleeding. Only 22·3% of patients underwent immune tolerance induction (ITI) treatment, of whom 64·9% achieved negative inhibitor titre. In patients who did not undergo ITI, the inhibitors turned negative in 17·7%, and patients with low peak inhibitor titre were more likely to acquire negative titre spontaneously (odds ratio 11·524, 95% confidence interval 5·222-25·432; P = 0·000). We recorded that 3·2% of the patients died from haemophilia-related life-threatening bleeding.
Assuntos
Fator VIII/imunologia , Hemofilia A/imunologia , Isoanticorpos/imunologia , Adolescente , Adulto , Idoso , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Fator VIII/uso terapêutico , Fator VIIa/uso terapêutico , Seguimentos , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemostáticos/provisão & distribuição , Hemostáticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Sistema de Registros , Índice de Gravidade de Doença , Adulto JovemRESUMO
AIM: To assess available evidence on the use of rFVIIa in non-orthopaedic surgery including dental surgery in adult patients with congenital haemophilia with inhibitors (PWHI). METHODS: A systematic literature search was performed according to a prespecified search string; prespecified criteria were used to select applicable studies including PWHI ≥18 years of age who underwent any non-orthopaedic surgery using rFVIIa. RESULTS: Thirty-three publications met the eligibility criteria, of which 26 publications - including 46 procedures in 44 patients - were selected for the qualitative analysis. Most publications were case reports or case series (21/26). Primary authors assessed rFVIIa as effective in maintaining haemostasis during and after most major surgeries (22/32). rFVIIa dose was mainly on label, with higher doses used in 4 cases, and a lower dose in 1 case. Duration of treatment was mostly 5-10 days (range: 3 days to 1 month post-operatively). Adverse events related to rFVIIa were rare. CONCLUSIONS: Assessing non-orthopaedic surgery in this patient population is hampered by a paucity of published data; nevertheless, the current evidence indicates that rFVIIa is effective in achieving haemostasis in haemophilia patients with inhibitors undergoing elective non-orthopaedic or dental surgery. rFVIIa was generally well tolerated in these patients, with thrombotic events occurring rarely. These data, generated to help clinicians manage congenital haemophilia with inhibitors, highlight the need for more systematic reporting of rFVIIa and all other therapeutic agents in non-orthopaedic surgery and dental surgery in patients with congenital haemophilia and inhibitors.
Assuntos
Hemofilia A , Adulto , Procedimentos Cirúrgicos Eletivos , Fator VIIa/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemofilia A/cirurgia , Humanos , Proteínas RecombinantesRESUMO
Treating patients with hemophilia and inhibitors is often problematic. The presence of inhibitors negatively impacts the effectiveness of treatment to achieve hemostasis especially in patients with hemophilia B, owing mainly to allergic reactions to factor IX (FIX) concentrates and the low success rate of immune tolerance therapy. A 9-month-old boy had intracranial hemorrhage and was diagnosed with hemophilia B. After replacement therapy, he developed inhibitors and an allergic reaction to FIX. Prophylactic therapy was initiated with recombinant activated factor VII (rFVIIa) and later switched to pdFVIIa/factor X (FX; 120 µg/kg as the FVII dose, every other day) because of a recurrence of intracranial hemorrhage. Since then, he remained well without life-threatening bleeding for more than 2 years. Our case suggests that pdFVIIa/FX may be useful for prophylactic therapy in hemophilia B complicated by inhibitors and allergic reaction to FIX concentrates.
Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Hemofilia B/tratamento farmacológico , Hipersensibilidade/diagnóstico , Fator IX/efeitos adversos , Fator IX/genética , Fator IX/uso terapêutico , Hemorragia , Humanos , Hipersensibilidade/etiologia , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study. METHODS: We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher's exact test was performed to compare categorical variables. Wilcoxon's rank-sum test was used to compare continuous variables between cohorts. RESULTS: Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005-3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3-12.3] versus 15.9 [15.1-17.2], p < 0.001) and international normalised ratio (0.8 [0.73-0.90] versus 1.3 [1.2-1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls. CONCLUSIONS: In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.
Assuntos
Transposição das Grandes Artérias , Fator VIIa , Fator VIIa/uso terapêutico , Humanos , Projetos Piloto , Estudos Prospectivos , Proteínas Recombinantes , Estudos RetrospectivosRESUMO
Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or systemic autoimmune disorders. Pathologic findings show pulmonary capillaritis, bland hemorrhage, diffuse alveolar damage, and hemosiderin-laden macrophages, but in the majority of cases, pathogenesis remains unclear. Despite the severity and high mortality, the current treatment options for DAH remain empirical. Systemic treatment to control inflammatory activity including high-dose corticosteroids, cyclophosphamide, and rituximab and supportive care have been applied, but largely unsuccessful in critical cases. Activated recombinant factor VII (FVIIa) can achieve rapid local hemostasis and has been administered either systemically or intrapulmonary for the treatment of DAH. However, there is no randomized controlled study to evaluate the efficacy and safety, and the use of FVIIa for DAH remains open to debate. This review discusses the pathogenesis, diverse etiologies causing DAH, diagnosis, and treatments focusing on hemostasis using FVIIa. In addition, the risks and benefits of the off-label use of FVIIa in pediatric patients will be discussed in detail.
Assuntos
Hemorragia/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Alvéolos Pulmonares/efeitos dos fármacos , Corticosteroides/uso terapêutico , Ciclofosfamida/uso terapêutico , Fator VIIa/uso terapêutico , Hemorragia/diagnóstico , Hemorragia/etiologia , Humanos , Inflamação/diagnóstico , Pneumopatias/diagnóstico , Pneumopatias/etiologia , Alvéolos Pulmonares/patologia , Proteínas Recombinantes/uso terapêutico , Rituximab/uso terapêuticoRESUMO
The authors report resection of anaplastic convexital meningioma in a middle-aged woman complicated by expected massive blood loss. The most intense bleeding occurred at the final stage of resection and it was impossible to stop it with traditional approaches. The surgeon pressed a standard tachocomb plate moistened with a diluted solution of recombinant activated factor VII (coagil, Russia) to the most bleeding area for 5 minutes. Subsequently, surgeon replaced finger pressure with a permanent napkin. Hemostatic effect of recombinant activated factor VII following its systemic administration is well known and convincingly proven in many surgical areas including neurosurgery. However, we do not know any descriptions of its local application in neurosurgical patients.