Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.122
Filtrar
1.
Medicine (Baltimore) ; 100(40): e27303, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622828

RESUMO

BACKGROUND: Hemophilia A (HA) is an inherited X-linked bleeding disease with costly treatment, especially for high titer inhibitory patients. Emicizumab, a new humanized bispecific antibody, has been approved for use to prevent or reduce the frequency of bleeding episodes in HA patients with inhibitors. This study evaluated the cost-utility of emicizumab prophylaxis (EP) in comparison with recombinant factor VII activated on-demand treatment in HA patients with inhibitors. METHODS: A life-time Markov model with payer and societal perspectives was developed in different age groups with different annual bleeding rates (ABR). Efficacy of treatments were extracted from HAVEN trials. Utilities were retrieved from published evidence. Costs were calculated based on Iran food and drug administration official website, national tariff book for medical services and hospital data. One-way deterministic sensitivity analysis was performed. RESULTS: EP was dominant choice in comparison with on-demand administration of recombinant factor VII activated in all age groups with ABR 20 and 25, and it remained dominant in patients with age 2 and age 12 at start point with ABR 16 and 17. The reported incremental cost-effectiveness ratio for the group with ABR 18 at the age 20, was 12,936 United States Dollars which is lower than the acceptable threshold of cost-effectiveness in Iran (1-3 gross domestic product per capita) and EP can be considered as cost-effective choice in this scenario. CONCLUSION: EP was found to be a dominant and cost-effective choice for Iranian HA patients with factor VIII inhibitors with ABR 18 and above with considerable cost saving.


Assuntos
Anticorpos Biespecíficos/economia , Anticorpos Monoclonais Humanizados/economia , Fator VIIa/economia , Hemofilia A/tratamento farmacológico , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Criança , Pré-Escolar , Análise Custo-Benefício , Fator VIIa/administração & dosagem , Feminino , Hemofilia A/economia , Hemorragia/prevenção & controle , Humanos , Irã (Geográfico) , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/economia , Adulto Jovem
2.
Haemophilia ; 27(6): 911-920, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34614267

RESUMO

INTRODUCTION: Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. AIM: To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. METHODS: Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. RESULTS: Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. CONCLUSION: Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.


Assuntos
Hemofilia A , Hemostáticos , Fator VIIa , Hemofilia A/tratamento farmacológico , Hemostasia , Hemostáticos/uso terapêutico , Humanos , Assistência Perioperatória , Proteínas Recombinantes
3.
Haemophilia ; 27(6): 921-931, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34636112

RESUMO

INTRODUCTION: Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS: Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 µg/kg EB initially followed by 75 µg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 µg/kg (minor procedures) or 200 µg/kg EB (major surgeries) with subsequent 75 µg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS: Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION: Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.


Assuntos
Hemofilia A , Adulto , Criança , Estudos Cross-Over , Fator VIIa/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemostasia , Humanos , Estudos Prospectivos , Proteínas Recombinantes
4.
Blood Coagul Fibrinolysis ; 32(7): 473-479, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34650021

RESUMO

Outcomes following administration of very-low-dose recombinant activated factor VIIa (vld-rFVIIa) for cardiac surgical bleeding remain debatable. We sought to determine the association of vld-rFVIIa and adverse surgical outcomes. Retrospective, cohort matching of patients undergoing cardiac surgery who received vld-rFVIIa (median 13.02 µg/kg) for perioperative bleeding were matched to cardiac surgical patients who had bleeding and received standard of care for bleeding without Factor VIIa administration. Of the 362 matched patients (182 in each group), patients who received rFVIIa required significantly less red blood cell transfusions [median 3 units (range 0--60, IQR = 4 units) versus 4 units (range 2-34, IQR = 4 units); P = 0.0004], decreased length of hospital stay (median 8 versus 9 days; P = 0.0158) and decreased renal risk (P < 0.0001). Incidence of renal failure, postoperative infection, postoperative thrombosis, prolonged ventilation, total ICU hours and 30-day mortality were not different between the two groups. Vld-rFVIIa for cardiac surgical bleeding was associated with decreased red blood cell transfusion, renal risk and length of hospital stay without increased thromboembolism or mortality when compared to patients who had cardiac surgical bleeding and received standard of care without Factor VIIa.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos , Transfusão de Eritrócitos , Fator VIIa/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Insuficiência Renal/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Relação Dose-Resposta a Droga , Fator VIIa/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal/etiologia , Estudos Retrospectivos , Adulto Jovem
5.
PLoS One ; 16(10): e0258192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614035

RESUMO

OBJECTIVES: Acquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models. METHODS: The first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis. RESULTS: In the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 µg/kg (therapeutic dose 90 µg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 µg/kg). CONCLUSIONS: These results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.


Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Trombose/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Fator VIIa/farmacologia , Feminino , Hemodiluição , Coelhos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Trombose/patologia , Fatores de Tempo , Ácido Tranexâmico/farmacologia
6.
J Card Surg ; 36(12): 4558-4563, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34608671

RESUMO

BACKGROUND: Use of recombinant activated factor VII (rFVIIa) to achieve hemostasis during cardiac surgery continues to be debated, as support for its efficacy and safety has not been consistent. We examined our experience with rFVIIa for achieving hemostasis in high-risk patients undergoing complex ascending aortic surgery. METHODS: We reviewed patients who underwent complex ascending aortic surgery performed by a single surgeon (C. K. R.) from August 2014 to February 2019. Outcomes of patients who received rFVIIa were compared with those who did not. RESULTS: Of 59 consecutive patients, 20 patients (33.9%) received rFVIIa, whereas 39 (66.1%) did not. Median dose was 45.4 mcg/kg. rFVIIa was administered intraoperatively to 95% of patients who received it. Most patients underwent combined aortic valve, ascending aorta, and aortic arch surgery (80.0% vs. 64.1%, p = .52). Patients receiving rFVIIa had longer mean cross clamp times (212 vs. 173 min, p = .03) and received a greater median number of intraoperative blood products (18.5 vs. 12.0, p < .001). The number of patients who needed postoperative products (75.0% vs. 60.5%, p = .39), the median number of blood products transfused postoperatively (2 vs. 2, p = .40), and chest tube output (1138 vs. 805 ml, p = .17) were similar between groups. In-hospital mortality was similar between groups (10.0% vs. 10.3%, p = 1.00). Incidences of postoperative stroke (10.0% vs. 13.5%, p = 1.00) and thromboembolic events (10.0% vs. 13.5%, p = 1.00) were similar. CONCLUSIONS: Administration of rFVIIa intraoperatively for refractory bleeding during complex ascending aortic surgery provided hemostasis without greater in-hospital mortality or a higher risk of stroke and thromboembolic events.


Assuntos
Fator VIIa , Cirurgiões , Hemostasia , Humanos , Hemorragia Pós-Operatória/epidemiologia , Proteínas Recombinantes , Estudos Retrospectivos
8.
Ann Clin Lab Sci ; 51(4): 546-551, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452894

RESUMO

OBJECTIVE: The factor VIIa-Antithrombin (VIIa-AT) complex is a relatively new biomarker associated with the activation of the extrinsic coagulation pathway. Since disseminated intravascular coagulation (DIC) is primarily driven by issue factor (TF)-induced extrinsic coagulation activation, the plasma level of factor VIIa-AT, via its role as an activation marker of the extrinsic pathway, could be a potential marker for DIC. The clinical significance of extrinsic coagulation markers, including factor VIIa-AT, in DIC was investigated. METHODS: The extrinsic coagulation markers, including factor VIIa-AT, TF, factor VII, and antithrombin (AT), were measured in 148 patients clinically suspicious for DIC. Multiple linear regression and Cox proportional-hazard analysis were conducted to evaluate both contributing factors and the prognostic power of the markers. RESULTS: The factor VIIa-AT complex, factor VII, and AT levels were significantly lower in the overt-DIC group and gradually decreased according to the severity of DIC based on the DIC scores. On the contrary, TF was significantly higher in the overt-DIC group. The factor VII level was revealed as a significant independent contributor to the factor VIIa-AT level. Upon multivariable Cox proportional-hazard analysis, the factor VIIa-AT complex showed the highest hazard ratio (3.41; 95% confidence interval 1.11-10.44). CONCLUSION: The factor VIIa-AT complex reflects the severity of DIC and is an independent prognostic factor of DIC. Our findings hint at the potential of the factor VIIa-AT complex to be used as a complementary marker to well-established biomarkers such as AT.


Assuntos
Antitrombinas/sangue , Biomarcadores/sangue , Coagulação Intravascular Disseminada/diagnóstico , Fator VIIa/análise , Estudos de Casos e Controles , Coagulação Intravascular Disseminada/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
10.
Artigo em Russo | MEDLINE | ID: mdl-34156209

RESUMO

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.


Assuntos
Fator VIIa/uso terapêutico , Hemostáticos , Neoplasias Meníngeas , Perda Sanguínea Cirúrgica , Feminino , Humanos , Neoplasias Meníngeas/cirurgia , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Federação Russa
11.
Blood ; 137(24): 3324-3325, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34137849
12.
Acta Crystallogr D Struct Biol ; 77(Pt 6): 809-819, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34076594

RESUMO

Coagulation factor VIIa (FVIIa) consists of a γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor-like (EGF) domains and a protease domain. FVIIa binds three Mg2+ ions and four Ca2+ ions in the GLA domain, one Ca2+ ion in the EGF1 domain and one Ca2+ ion in the protease domain. Further, FVIIa contains an Na+ site in the protease domain. Since Na+ and water share the same number of electrons, Na+ sites in proteins are difficult to distinguish from waters in X-ray structures. Here, to verify the Na+ site in FVIIa, the structure of the FVIIa-soluble tissue factor (TF) complex was solved at 1.8 Šresolution containing Mg2+, Ca2+ and Rb+ ions. In this structure, Rb+ replaced two Ca2+ sites in the GLA domain and occupied three non-metal sites in the protease domain. However, Rb+ was not detected at the expected Na+ site. In kinetic experiments, Na+ increased the amidolytic activity of FVIIa towards the synthetic substrate S-2288 (H-D-Ile-Pro-Arg-p-nitroanilide) by ∼20-fold; however, in the presence of Ca2+, Na+ had a negligible effect. Ca2+ increased the hydrolytic activity of FVIIa towards S-2288 by ∼60-fold in the absence of Na+ and by ∼82-fold in the presence of Na+. In molecular-dynamics simulations, Na+ stabilized the two Na+-binding loops (the 184-loop and 220-loop) and the TF-binding region spanning residues 163-180. Ca2+ stabilized the Ca2+-binding loop (the 70-loop) and Na+-binding loops but not the TF-binding region. Na+ and Ca2+ together stabilized both the Na+-binding and Ca2+-binding loops and the TF-binding region. Previously, Rb+ has been used to define the Na+ site in thrombin; however, it was unsuccessful in detecting the Na+ site in FVIIa. A conceivable explanation for this observation is provided.


Assuntos
Cálcio/metabolismo , Fator VIIa , Magnésio/metabolismo , Rubídio/metabolismo , Sítios de Ligação , Fator VIIa/química , Fator VIIa/metabolismo , Humanos , Ligação Proteica , Domínios Proteicos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
13.
Mil Med ; 186(7-8): 829-831, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33885819

RESUMO

Factor VII (FVII) deficiency is a hereditary bleeding disorder that significantly increases the risk of hemorrhage during the intrapartum and postpartum periods as well as during surgery. Management often requires careful pre- and post-operative planning, a multi-disciplinary approach, and management at a tertiary center. Most cases in the literature utilized recombinant FVII for treatment. We present a case of a young active duty female who had an undiagnosed FVII deficiency that became apparent during her expedited delivery for fetal distress. Our patient was admitted for delivery while undergoing a work up for an abnormal coagulation panel. Given high suspicion for FVII deficiency, anticipated hemorrhage, and need for cesarean delivery, she was treated with blood products containing FVII. Two days after delivery her diagnosis was confirmed. Available literature discusses the management of known FVII deficiency in pregnancy; however, to the best of our knowledge, there are no cases of an unknown bleeding diathesis incidentally identified just before delivery and later diagnosed as FVII deficiency. This case highlights the appropriate management of an unknown coagulopathy, the significant challenges associated, and the incorporation of a multi-disciplinary team critical to reducing significant maternal morbidity.


Assuntos
Deficiência do Fator VII , Militares , Hemorragia Pós-Parto , Fator VIIa , Feminino , Humanos , Gravidez , Proteínas Recombinantes
14.
Biomolecules ; 11(4)2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917935

RESUMO

The vast majority of coagulation factor VII (FVII), a trypsin-like protease, circulates as the inactive zymogen. Activated FVII (FVIIa) is formed upon proteolytic activation of FVII, where it remains in a zymogen-like state and it is fully activated only when bound to tissue factor (TF). The catalytic domains of trypsin-like proteases adopt strikingly similar structures in their fully active forms. However, the dynamics and structures of the available corresponding zymogens reveal remarkable conformational plasticity of the protease domain prior to activation in many cases. Exactly how ligands and cofactors modulate the conformational dynamics and function of these proteases is not entirely understood. Here, we employ atomistic simulations of FVIIa (and variants hereof, including a TF-independent variant and N-terminally truncated variants) to provide fundamental insights with atomistic resolution into the plasticity-rigidity interplay of the protease domain conformations that appears to govern the functional response to proteolytic and allosteric activation. We argue that these findings are relevant to the FVII zymogen, whose structure has remained elusive despite substantial efforts. Our results shed light on the nature of FVII and demonstrate how conformational dynamics has played a crucial role in the evolutionary adaptation of regulatory mechanisms that were not present in the ancestral trypsin. Exploiting this knowledge could lead to engineering of protease variants for use as next-generation hemostatic therapeutics.


Assuntos
Fator VII/química , Fator VIIa/química , Precursores de Proteínas/química , Regulação Alostérica , Domínio Catalítico , Análise por Conglomerados , Fator VII/metabolismo , Fator VIIa/metabolismo , Humanos , Simulação de Dinâmica Molecular , Análise de Componente Principal , Precursores de Proteínas/metabolismo , Estrutura Terciária de Proteína , Tromboplastina/química , Tromboplastina/metabolismo , Tripsina/metabolismo
15.
J Thromb Haemost ; 19(7): 1687-1696, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33819375

RESUMO

BACKGROUND: The anti-tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX). OBJECTIVES: To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential. METHODS: Pooled HA plasma was spiked in vitro with concizumab alone or together with rFVIIa, APCC, or rFVIII. rFVIIa, APCC, and rFVIII were added ex vivo to plasma from HA patients receiving concizumab prophylaxis. Pooled HB plasma was spiked with concizumab alone or together with rFIX. TG potential was measured after initiation with tissue factor. RESULTS: Concizumab increased thrombin peak in a concentration-dependent manner. Adding rFVIIa, APCC, rFVIII, or rFIX caused a further increase in thrombin peak. The effects of concizumab and rFVIIa, APCC, rFVIII, or rFIX were mainly additive, with no or up to maximally ~25% extra effect caused by drug--drug interaction. No strong synergistic effects were observed upon combining concizumab with rFVIIa, APCC, rFVIII, or rFIX. The thrombin peak obtained with 0.5 IU/ml rFVIII or rFIX in the presence of concizumab was on occasion slightly higher, but mostly comparable to the thrombin peak with 1 IU/ml rFVIII or rFIX in the absence of concizumab. CONCLUSION: rFVIIa, APCC, rFVIII, and rFIX enhanced plasma TG potential in the presence of concizumab. Dose levels of concomitant use should be adjusted accordingly to balance potential safety concerns while maintaining the necessary hemostatic effect. Please see the video in the Supplementary Material for an animated summary of the data presented.


Assuntos
Fator VIIa , Hemofilia A , Anticorpos Monoclonais Humanizados , Fatores de Coagulação Sanguínea , Fator IX , Fator VIII , Hemofilia A/tratamento farmacológico , Humanos , Proteínas Recombinantes , Trombina
16.
Blood Coagul Fibrinolysis ; 32(5): 349-351, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33878047

RESUMO

Glanzmann thrombasthenia is an inherited disease causing bleeding episodes due to platelet dysfunction. The standard treatment for moderate-severe bleeding is platelet transfusion. Recombinant factor VIIa (rFVIIa) is successfully used in bleeding episodes and invasive procedures. Here, we present a patient with Glanzmann thrombasthenia, whose bleeding episodes could only be controlled by rFVIIa. The patient is a 28 years old male, who has had frequent bleeding episodes unresponsive to local hemostatic agents and tranexamic acid and had an anaphylactoid reaction to platelet transfusion. We started the patient on a low-dose (20 µg/kg) rFVIIa once a week. The patient has no spontaneous bleeding since then. This is the first case report of a Glanzmann thrombasthenia patient on routine prophylaxis with low-dose rFVIIa.


Assuntos
Fator VIIa/uso terapêutico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Trombastenia/complicações , Adulto , Relação Dose-Resposta a Droga , Fator VIIa/administração & dosagem , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
17.
J Thromb Haemost ; 19(8): 1932-1947, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830628

RESUMO

BACKGROUND: CD248 is a pro-inflammatory, transmembrane glycoprotein expressed by vascular smooth muscle cells (VSMC), monocytes/macrophages, and other cells of mesenchymal origin. Its distribution and properties are reminiscent of those of the initiator of coagulation, tissue factor (TF). OBJECTIVE: We examined whether CD248 also participates in thrombosis. METHODS: We evaluated the role of CD248 in coagulation using mouse models of vascular injury, and by assessing its functional interaction with the TF-factor VIIa (FVIIa)-factor X (FX) complex. RESULTS: The time to ferric chloride-induced occlusion of the carotid artery in CD248 knockout (KO) mice was significantly longer than in wild-type (WT) mice. In an inferior vena cava (IVC) stenosis model of thrombosis, lack of CD248 conferred relative resistance to thrombus formation compared to WT mice. Levels of circulating cells and coagulation factors, prothrombin time, activated partial thromboplastin time, and tail bleeding times were similar in both groups. Proximity ligation assays revealed that TF and CD248 are <40 nm apart, suggesting a potential functional relationship. Expression of CD248 by murine and human VSMCs, and by a monocytic cell line, significantly augmented TF-FVIIa-mediated activation of FX, which was not due to differential expression or encryption of TF, altered exposure of phosphatidylserine or differences in tissue factor pathway inhibitor expression. Rather, conformation-specific antibodies showed that CD248 induces allosteric changes in the TF-FVIIa-FX complex that facilitates FX activation by TF-FVIIa. CONCLUSION: CD248 is a newly uncovered protein partner and potential therapeutic target in the TF-FVIIa-FX macromolecular complex that modulates coagulation.


Assuntos
Tromboplastina , Trombose Venosa , Animais , Antígenos CD , Antígenos de Neoplasias , Fator VIIa , Humanos , Camundongos , Camundongos Knockout , Tempo de Protrombina
18.
Blood Coagul Fibrinolysis ; 32(6): 418-422, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33859115

RESUMO

Hemorrhage in the central nervous system is the most severe and debilitating manifestation affecting patients with hemophilia A. The spinal epidural space is the most unusual and clinically challenging site of central nervous system hemorrhage in hemophilia A. These patients often show insidious neurological signs and symptoms that delay diagnosis and treatment. We share our experience treating a 4-year-old male patient with severe hemophilia A and high titer inhibitors with a spontaneous spinal epidural hematoma. The patient presented initially with intense headache and neck pain. After blood tests and imaging studies, bypassing agent therapy with recombinant-activated factor VII was used until discharge; this was later replaced with emicizumab. After 18 months, the patient is without neurological sequelae and has not experienced subsequent bleeding episodes. We review the available literature and discuss the relevance of emicizumab compared with standard therapies in the context of spontaneous spinal epidural hematoma.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fator VIIa/uso terapêutico , Hematoma Epidural Espinal/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Pré-Escolar , Hematoma Epidural Espinal/etiologia , Hemofilia A/complicações , Hemorragia/prevenção & controle , Humanos , Masculino , Proteínas Recombinantes/uso terapêutico
19.
Haemophilia ; 27(3): e314-e330, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33751769

RESUMO

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 Recombinantes
20.
Rev. colomb. anestesiol ; 49(1): e600, Jan.-Mar. 2021. graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1149800

RESUMO

Abstract Introduction Glanzmann thromboasthenia is a rare congenital bleeding disorder caused by a mutation in platelet glycoprotein α-IIb and β3 encoding genes (ITGA2B; 607759 and ITGB3; 173470) in chromosomes I7q21.31 and 17q21.32, respectively, which results in a qualitative or quantitative alteration of the platelet integrin αIIbβ3 (glycoprotein IIb/IIIa) receptor. Glanzmann thromboasthenia is classified as type I when less than 5% of glycoprotein αIIbβ3 is expressed, and as type II when more than 5% is expressed. Case presentation Description of the perioperative management of a 13-year-old female patient with Glanzmann thromboasthenia who underwent endoscopic anterior bilateral ethmoidectomy. Management was centered on prophylactic platelet transfusion plus the use of tranexamic acid, as well as thromboelastographic determination of hemostasis. There were no bleeding complications during or after the procedure. Conclusiones Pediatric patients with Glanzmann thromboasthenia are at a high risk of perioperastive bleeding. Platelet transfusion is the best prophylactic and therapeutic alternative; however, even in the absence of anti-platelet antibodies, it may not be effective, and viscoelastic testing must be used for assessment during the surgical procedure in order to improve patient safety.


Resumen Introducción La trombastenia de Glanzmann es un trastorno hemorrágico congénito infrecuente, causado por mutación en los genes que codifican las glucoproteínas plaquetarias α-IIb (ITGA2B; 607759) y β3 (ITGB3; 173470) en los cromosomas I7q2i.3i y I7q2i.32, respectivamente, alterando cualitativa o cuantitativamente al receptor plaquetario de integrina αIIbβ3 (glucoproteína IIb/IIIa). La trombastenia de Glanzmann se clasifica como tipo I cuando se expresa menos del 5 % de la glucoproteína αIIbβ3 y como tipo II, cuando es mayor al 5 %. Presentación del caso Se describe el manejo perioperatorio de una paciente de 13 años de edad con trombastenia de Glanzmann, sometida a etmoidectomía anterior bilateral endoscópica. El manejo se centró en la transfusión profiláctica de plaquetas y ácido tranexámico, así como en la evaluación de la hemostasia con tromboelastografía. No hubo complicaciones hemorrágicas durante y después del procedimiento. Conclusiones Los pacientes pediátricos con trombastenia de Glanzmann tienen alto riesgo de hemorragia perioperatoria. La transfusión de plaquetas es la mejor alternativa profiláctica y terapéutica; sin embargo, incluso en ausencia de anticuerpos antiplaquetarios, puede no ser efectiva y debe evaluarse mediante pruebas viscoelásticas durante los procedimientos quirúrgicos para mejorar la seguridad del paciente.


Assuntos
Humanos , Feminino , Adolescente , Trombastenia , Fator VIIa , Tromboelastografia , Transfusão de Plaquetas , Deficiência do Fator VII , Doenças Genéticas Inatas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...