RESUMEN
For patients with hemophilia A and high-titer inhibitors treated with bypassing agents there are no reliable methods to assess treatment effect. We investigated the utility of global hemostatic methods in assessing treatment with bypassing agents (rFVIIa or activated prothrombin complex [aPCC]). All patients with hemophilia A and inhibitors followed at the Coagulation Unit or the Pediatric Coagulation Unit at Karolinska University Hospital aged 6 years and above were eligible for this noninterventional study. Baseline plasma samples were spiked with bypassing agents in increasing concentrations (aPCC 50 U/kg, 100 U/kg, 150 U/kg, and rFVIIa 90 µg/kg and 270 µg/kg) in vitro. For patients treated with factor concentrates or bypassing agents follow-up samples were collected (in vivo tests). The samples were analyzed using overall hemostatic potential (OHP), and calibrated automated thrombogram, Calibrated Automated Thrombogram (CAT). Nine patients with hemophilia A with inhibitors were included. Spiking with rFVIIa normalized the coagulation potential in 6/8 samples, in 3 only with high dose. Only one sample did not improve adequately after spiking with aPCC. The improvement in hemostasis was reliably shown by both CAT and OHP. The baseline potential was, however, more often measurable by OHP compared to CAT. Factor concentrate had been administered to 5 patients normalizing the hemostatic potential in vivo in 2 (without spiking). The hemostatic improvement induced by spiking with rFVIIa or aPCC is shown by OHP and CAT, but the results have to be evaluated in larger cohorts.
Asunto(s)
Factor VIIa , Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Proyectos Piloto , Niño , Masculino , Factor VIIa/farmacología , Factor VIIa/uso terapéutico , Adolescente , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/farmacología , Hemostasis/efectos de los fármacos , Factores de Coagulación Sanguínea/farmacología , Factores de Coagulación Sanguínea/uso terapéutico , Hemostáticos/uso terapéutico , Hemostáticos/farmacología , Adulto , FemeninoRESUMEN
BACKGROUND: The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding. AIM AND METHODS: We identified 'unresponsiveness' to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions. RESULTS: Our data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 µg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL). CONCLUSIONS: Unresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy.
Asunto(s)
Anticuerpos Biespecíficos , Anticuerpos Monoclonales Humanizados , Factor VIIa , Factor X , Hemofilia A , Hemostasis , Proteínas Recombinantes , Femenino , Humanos , Masculino , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Coagulación Sanguínea/efectos de los fármacos , Factor VIIa/farmacología , Factor VIIa/uso terapéutico , Factor X/metabolismo , Hemofilia A/tratamiento farmacológico , Hemofilia A/sangre , Hemostasis/efectos de los fármacos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , TromboelastografíaRESUMEN
ABSTRACT: The hemostatic system is upregulated to protect pregnant mothers from hemorrhage during childbirth. Studies of the details just before and after delivery, however, are lacking. Recombinant factor VIIa (rFVIIa) has recently been granted approval by the European Medicines Agency for the treatment of postpartum hemorrhage (PPH). A next-generation molecule, CT-001, is being developed as a potentially safer and more efficacious rFVIIa-based therapy. We sought to evaluate the peripartum hemostatic status of pregnant women and assess the ex vivo hemostatic activity of rFVIIa and CT-001 in peripartum blood samples. Pregnant women from 2 study sites were enrolled in this prospective observational study. Baseline blood samples were collected up to 3 days before delivery. Postdelivery samples were collected 45 (±15) minutes after delivery. Between the 2 time points, soluble fibrin monomer and D-dimer increased whereas tissue factor, FVIII, FV, and fibrinogen decreased. Interestingly, the postdelivery lag time and time to peak in the thrombin generation assay were shortened, and the peak thrombin generation capacity was maintained despite the reduced levels of coagulation proteins after delivery. Furthermore, both rFVIIa and CT-001 were effective in enhancing clotting activity of postdelivery samples in activated partial thromboplastin time, prothrombin time, thrombin generation, and viscoelastic hemostatic assays, with CT-001 demonstrating greater activity. In conclusion, despite apparent ongoing consumption of coagulation factors at the time of delivery, thrombin output was maintained. Both rFVIIa and CT-001 enhanced the upregulated hemostatic activity in postdelivery samples, and consistent with previous studies comparing CT-001 and rFVIIa in vitro and in in vivo, CT-001 demonstrated greater activity than rFVIIa.
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Hemostáticos , Hemorragia Posparto , Femenino , Humanos , Embarazo , Factores de Coagulación Sanguínea , Factor VIIa/farmacología , Hemostáticos/farmacología , Periodo Posparto , Trombina , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a prohemostatic therapeutic intervention should take this thrombotic risk into consideration. OBJECTIVES: CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss. METHODS: The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC pathway-induced coagulopathic conditions were assessed by coagulation assays and bleeding models. RESULTS: The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype FVIIa. CT-001 corrected the activated partial thromboplastin time and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg of CT-001 reduced bleeding time in comparison with wildtype FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid, and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity. CONCLUSION: CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective procoagulant agent for addressing APC-mediated bleeding.
Asunto(s)
Trastornos de la Coagulación Sanguínea , Ácido Tranexámico , Humanos , Ratones , Ratas , Animales , Proteína C/farmacología , Proteína C/uso terapéutico , Ácido Tranexámico/uso terapéutico , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea/etiología , Hemostasis , Hemorragia , Factor VIIa/uso terapéutico , Factor VIIa/farmacología , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Preclinical bleeding models increase current hemophilia A (HA) knowledge and aid the development of new pharmacological treatments. There are several well-established mouse bleeding models, but limited options are available for rat models despite their high resemblance to human disease process. OBJECTIVE: To provide a comprehensive description of the tail vein transection (TVT) bleeding model in HA rats and examine the correlation between in vivo pharmacological efficacy and global hemostatic assays. METHODS: The TVT bleeding model was implemented in HA rats and used to perform dose-response studies with recombinant coagulation factors VIIa (rFVIIa) and VIII (rFVIII). After the TVT bleeding model, whole blood and plasma were collected from rats and evaluated with thrombin generation test (TGT) and rotational thromboelastometry (ROTEM). RESULTS: Using the TVT bleeding model, the potency of rFVIII and rFVIIa treatments in HA rats were assessed, and the pharmacological windows established for rFVIII (≤15 U/kg) and rFVIIa (≤2.7 mg/kg). ED50 was estimated to be 1.75 U/kg for rFVIII and 0.37 mg/kg for rFVIIa, whereas complete normalization was observed with 15 U/kg and 2.7 mg/kg respectively. Furthermore, responses to rFVIII and rFVIIa in the TGT and ROTEM assays strongly correlated to in vivo pharmacological efficacy. CONCLUSION: The TVT bleeding model in HA rats is a useful tool to assess the pharmacodynamic effects of hemostatic compounds in vivo, and strongly correlates to results obtained with TGT and ROTEM in HA rats, adding further value to the HA rat model in preclinical research.
Asunto(s)
Hemofilia A , Hemostáticos , Humanos , Ratones , Ratas , Animales , Hemofilia A/tratamiento farmacológico , Factor VIIa/farmacología , Factor VIII/farmacología , Hemorragia/tratamiento farmacológico , Proteínas Recombinantes/farmacología , Hemostáticos/farmacología , Modelos Animales de EnfermedadRESUMEN
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.
Asunto(s)
Hemofilia A , Hemofilia B , Humanos , Masculino , Factor X/uso terapéutico , Factor X/farmacología , Hemofilia B/complicaciones , Hemofilia B/tratamiento farmacológico , Factor VIIa/uso terapéutico , Factor VIIa/farmacología , Estudios Prospectivos , Hemorragia/prevención & control , Hemorragia/tratamiento farmacológico , Hemofilia A/tratamiento farmacológico , Factor VIII/uso terapéuticoRESUMEN
INTRODUCTION: Acute bleeding leads to significant morbidity and mortality. Recombinant wildtype Factor VIIa (WT FVIIa) had been reported to have some therapeutic effects in some clinical trials, however, its use was associated with thromboembolic events. We sought to develop a novel FVIIa molecule (CT-001) with enhanced activity and lowered thrombogenicity risk. METHODS AND METHODS: CT-001 has 4 N-glycans (T106N/N145/V253N/N322) with terminal sialic acid residues removed to promote active clearance via the asialoglycoprotein receptor, and P10Q/K32E substitutions introduced to its gamma-carboxyglutamic acid (Gla) domain for enhanced phospholipid affinity and activity. RESULTS: In mice, CT-001 had a half-life of 5 min and a clearance of 467 mL/h/kg at 3 mg/kg, significantly faster than WT FVIIa (t1/2 = 1.8 h, Cl = 39 mL/h/kg). Interestingly, CT-001 was efficacious in reducing blood loss even with its rapid clearance. In a severe hemorrhage mouse model with tail amputated 5 cm from the tip, 1 mg/kg CT-001 provided efficacy comparable to 3 mg/kg WT FVIIa. The fast clearance of CT-001 resulted in significantly reduced thrombogenicity in comparison to WT FVIIa in a FeCl3-induced carotid artery thrombosis mouse model, and further confirmed in a soluble tissue factor-induced thrombosis model. CONCLUSIONS: The data on CT-001 demonstrate that a short duration of highly active FVIIa procoagulant activity has the potential to be an optimal paradigm for the treatment of acute bleeds.
Asunto(s)
Factor VIIa , Hemostáticos , Animales , Modelos Animales de Enfermedad , Factor VIIa/farmacología , Factor VIIa/uso terapéutico , Hemorragia/tratamiento farmacológico , Humanos , Ratones , Tromboplastina , Tomografía Computarizada por Rayos XRESUMEN
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.
Asunto(s)
Factores de Coagulación Sanguínea/metabolismo , Trombosis/metabolismo , Animales , Arterias/efectos de los fármacos , Arterias/patología , Factor VIIa/farmacología , Femenino , Hemodilución , Conejos , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Trombosis/patología , Factores de Tiempo , Ácido Tranexámico/farmacologíaRESUMEN
Recombinant factor FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1-mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type (WT), EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice. In vivo studies revealed that administration of FVIIa to WT, EPCR-overexpressing, and PAR1-R46Q-mutant mice, but not EPCR-deficient or PAR1-R41Q-mutant mice, increased the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.
Asunto(s)
Endotelio Vascular/metabolismo , Vesículas Extracelulares/metabolismo , Factor VIIa/farmacología , Hemostasis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Receptor PAR-1/metabolismo , Sustitución de Aminoácidos , Animales , Vesículas Extracelulares/genética , Hemostasis/genética , Humanos , Ratones , Ratones Noqueados , Mutación Missense , Receptor PAR-1/genética , Proteínas Recombinantes/farmacologíaRESUMEN
: Bleeding among critically ill paediatric haematology/oncology (CIPHO) patients leads to significant morbidity and mortality. Recombinant activated factor VII (rFVIIa) has shown some benefits in previous reported off-label use when conventional therapies have failed. However, data in CIPHO are lacking. We retrospectively studied (2006-2014) the efficacy and outcomes in CIPHO patients younger than 21 years who received at least one rFVIIa dose for bleeding in the ICU. Of 39 patients, the majority had leukaemia (59%), bone marrow transplantation (77%) and a life-threatening bleed (80%) with most common site being pulmonary haemorrhage (44%). Most needed invasive mechanical ventilation (87%) or vasopressor support (59%). After rFVIIa administration, 56% had cessation or decreased bleeding. Packed red blood cell transfusion requirements decreased significantly 48-72âh after rFVIIa administration. Lower baseline prothrombin time and more rFVIIa doses were related to bleeding control. A favourable response was associated with higher survival (55% in responders versus 18% in nonresponders, Pâ=â0.019). Overall, bleeding-related mortality was 37.5%, highest in pulmonary haemorrhage. Two patients had thromboembolic events. Use of rFVIIa for CIPHO patients appears to be well tolerated with low adverse events. Despite half of the patients having a favourable response of cessation or decrease in bleeding after rFVIIa administration, mortality was high. These findings highlight the need for prospective studies to evaluate interventions to improve outcomes in this population.
Asunto(s)
Factor VIIa/uso terapéutico , Hemorragia/tratamiento farmacológico , Niño , Factor VIIa/farmacología , Femenino , Hemorragia/sangre , Humanos , Unidades de Cuidado Intensivo Pediátrico , MasculinoRESUMEN
The tissue factor/coagulation factor VIIa (TF/FVIIa) complex induces transactivation of the IGF-1 receptor (IGF-1R) in a number of different cell types. The mechanism is largely unknown. The transactivation leads to protection from apoptosis and nuclear translocation of the IGF-1R. The aim of this study was to clarify the signaling pathway between TF and IGF-1R after FVIIa treatment with PC3 and DU145 prostate or MDA-MB-231 breast cancer cells as model systems. Protein interactions, levels, and phosphorylations were assessed by proximity ligation assay or flow cytometry in intact cells and by western blot on cell lysates. The transactivation of the IGF-1R was found dependent on TF/FVIIa-induced activation of ß1-integrins. A series of experiments led to the conclusion that the caveolae protein caveolin-1 prevented IGF-1R activation in resting cells via its scaffolding domain. TF/FVIIa/ß1-integrins terminated this inhibition by activation of Src family kinases and subsequent phosphorylation of caveolin-1 on tyrosine 14. This phosphorylation was not seen after treatment with PAR1 or PAR2 agonists. Consequently, the protective effect of FVIIa against apoptosis induced by the death receptor agonist TRAIL and the de novo synthesis of cyclin D1 induced by nuclear IGF-1R accumulation were both significantly reduced by down-regulation of ß1-integrins or overexpression of the caveolin-1 scaffolding domain. In conclusion, we present a plausible mechanism for the interplay between TF and IGF-1R involving FVIIa, ß1-integrins, Src family proteins, and caveolin-1. Our results increase the knowledge of diseases associated with TF and IGF-1R overexpression in general but specifically of TF-mediated signaling with focus on cell survival.
Asunto(s)
Caveolina 1/genética , Factor VIIa/farmacología , Regulación Neoplásica de la Expresión Génica , Integrina beta1/genética , Receptor IGF Tipo 1/genética , Tromboplastina/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Caveolas/efectos de los fármacos , Caveolas/metabolismo , Caveolina 1/metabolismo , Línea Celular Tumoral , Supervivencia Celular/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Factor VIIa/genética , Factor VIIa/metabolismo , Humanos , Integrina beta1/metabolismo , Fosforilación , Transporte de Proteínas/efectos de los fármacos , Receptor IGF Tipo 1/metabolismo , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Tromboplastina/genética , Tromboplastina/metabolismo , Activación Transcripcional/efectos de los fármacos , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismoRESUMEN
In emicizumab prophylaxis, the concomitant therapy using bypassing agents (BPAs) is required for breakthrough bleeding and invasive procedures with attention to thrombotic complications. To predict coagulant effects of BPAs in emicizumab-treated patients with haemophilia A (PwHA) with inhibitor (PwHAwI), blood samples from emicizumab-treated PwHAwI (n = 8) and PwHA without inhibitor (n = 2) in phase 1/2 and HAVEN 1 study, spiked with activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa) ex vivo, and blood samples from emicizumab-treated PwHAwI-receiving BPAs were analysed by Ca2+ -triggered rotational thromboelastometry (ROTEM) and ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Spiked aPCC, corresponded to 10-100 U/kg, markedly shortened ROTEM parameters beyond the normal range, while spiked rFVIIa, corresponded to 90-270 µg/kg, shortened them within near-normal range. Each of the spiked BPA-improved adjusted maximum coagulation velocity of CWA to within or near the normal range. In blood samples at post-infusion of aPCC (44-73 U/kg) or rFVIIa (79-93 µg/kg), the parameters of both assays improved to approximately the normal range. Taken together, ex vivo results of spiking tests in ROTEM and CWA, except aPCC spiking test in ROTEM, were relatively consistent with in vivo ones, and could usefully predict the coagulant effects of concomitant bypassing therapy for emicizumab-treated PwHAwI.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Inhibidores de Factor de Coagulación Sanguínea/sangre , Hemofilia A , Adulto , Factor VIIa/farmacología , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacología , TromboelastografíaRESUMEN
A combined product of plasma-derived factor (F)VIIa and FX (pd-FVIIa/FX; Byclot®) is currently available for the hemostatic treatment of hemophilia A and B patients with inhibitors in Japan. Limited information is available, however, on its coagulant effect in acquired hemophilia A (AHA). In the present study, we assessed the coagulant effect of pd-FVIIa/FX on impairment of coagulation potentials in AHA. The bypassing agents, pd-FVIIa/FX, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrates (aPCC) were spiked with normal plasma preincubated with anti-FVIII monoclonal antibody (AHA-model plasma), and added to plasmas from AHA patients. Clot waveform analysis (CWA) triggered by the mixture of tissue factor and ellagic acid was subsequently performed. In the AHA-model, pd-FVIIa/FX improved all of the CWA parameters in a dose-dependent manner, irrespective of epitope specificity, with significant improvements relative to rFVIIa and aPCC. The coagulant effect of pd-FVIIa/FX at 1.6 µg/mL (corresponding to 120 µg/kg infusion) at the maximum therapeutic dose was outside the normal range. Moreover, the addition of pd-FVIIa/FX led to a greater improvement in the coagulant potentials in AHA plasmas than those of rFVIIa and/or aPCC. These data suggest that pd-FVIIa/FX significantly improves the impaired coagulant potentials in AHA and is potentially therapeutic.
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Coagulación Sanguínea/efectos de los fármacos , Coagulantes , Factor VIIa/farmacología , Factor X/farmacología , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Factor VIIa/uso terapéutico , Factor X/uso terapéutico , Humanos , Técnicas In VitroRESUMEN
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 (30â IU/kg plasma-derived FVII [pdFVII] or 25â µg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300â µg/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48â 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 4.5â 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 ≥8â hr.Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.
Asunto(s)
Deficiencia del Factor VII/tratamiento farmacológico , Factor VIIa/uso terapéutico , Adulto , Coagulación Sanguínea/efectos de los fármacos , Deficiencia del Factor VII/sangre , Factor VIIa/efectos adversos , Factor VIIa/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/sangre , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Albúmina Sérica Humana/efectos adversos , Albúmina Sérica Humana/análisis , Albúmina Sérica Humana/farmacología , Albúmina Sérica Humana/uso terapéutico , Resultado del Tratamiento , Adulto JovenAsunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Factor VIIa/uso terapéutico , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Embolia Pulmonar/etiología , Infarto del Miocardio con Elevación del ST/etiología , Adulto , Anticuerpos Biespecíficos/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Factor VIIa/farmacología , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Factor VIIa/farmacología , Hemofilia A/complicaciones , Hemofilia A/inmunología , Hemorragia/tratamiento farmacológico , Factor VIIa/inmunología , Factor VIIa/uso terapéutico , Hemorragia/complicaciones , Hemorragia/prevención & control , Humanos , IncertidumbreRESUMEN
Vatreptacog alfa (VA), a recombinant activated human factor VII (rFVIIa) variant with 3 amino acid substitutions, was developed to provide increased procoagulant activity in hemophilia patients with inhibitors to factor VIII or factor IX. In phase 3 clinical trials, changes introduced during the bioengineering of VA resulted in the development of undesired anti-drug antibodies in some patients, leading to the termination of a potentially promising therapeutic protein product. Here, we use preclinical biomarkers associated with clinical immunogenicity to validate our deimmunization strategy applied to this bioengineered rFVIIa analog. The reengineered rFVIIa analog variants retained increased intrinsic thrombin generation activity but did not elicit T-cell responses in peripheral blood mononuclear cells isolated from 50 HLA typed subjects representing the human population. Our algorithm, rational immunogenicity determination, offers a broadly applicable deimmunizing strategy for bioengineered proteins.