Eptacog Beta for Bleeding Treatment and Prevention in Congenital Hemophilia A and B With Inhibitors: A Review of Clinical Data and Implications for Clinical Practice.

OBJECTIVE: To review the pharmacology, dosing and administration, safety, clinical efficacy, and role of eptacog beta in the treatment of congenital hemophilia with inhibitors. DATA SOURCES: A literature search of PubMed (1966 to August 2021) was conducted using the keywords eptacog beta, recombinant FVII, and hemophilia. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and prescribing information on eptacog beta for the treatment of congenital hemophilia with inhibitors were reviewed. DATA SYNTHESIS: Eptacog beta is a novel recombinant activated factor VII (rVIIa) product that demonstrated efficacy in controlling bleeding and associated pain in patients with hemophilia A or B with inhibitors. Eptacog beta has limited Food and Drug Administration-approved and off-label indications compared with other bypassing agents (BPAs; activated prothrombin complex concentrates [aPCC; eptacog alfa]). Eptacog beta costs less than eptacog alfa, but still more than aPCCs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review provides insight into the role of eptacog beta for treatment of congenital hemophilia with inhibitors and reviews important health system formulary considerations for available BPAs. CONCLUSIONS: Eptacog beta is more cost-effective than eptacog alfa and, as such, may become the preferred rVIIa formulary product. However, eptacog alfa availability remains necessary for the treatment of disorders where eptacog beta has limited data. aPCC should remain the first-line BPA for the treatment of bleeding in patients with inhibitors with no contraindications to use because of its equivocal efficacy and safety and in light of the magnitude of cost savings associated with this strategy.

Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male.

BACKGROUND: In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. CASE: A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement. Genotyping showed the rare heterozygous FVII 9729del4 mutation. Bleed evacuation was complicated by epidural abscess requiring craniectomy, bone graft procedures, and prolonged administration of recombinant human (rh) activated FVII (FVIIa). The patient recovered without neurological deficits, and remains on prophylactic low dose treatment with rhFVIIa in relation to risky athletic activities. CONCLUSION: For clinicians, it is important to recognize that effects of rhFVIIa within these pathways are independent of its contribution to blood clot formation and cannot be assessed by clotting assays. Reduced FVII levels should therefore not be dismissed, as even a mild reduction may result in spontaneous bleeding. Treatment of mild FVII deficiency requires a careful case-by-case approach, based on the clinical scenario.

Site-directed mutagenesis of tissue factor pathway inhibitor-binding exosite D60A on factor VII results in a new factor VII variant with lower coagulant activity.

Background: Recombinant factor (F)VIIa (rFVIIa) has been approved by the US Food and Drug Administration for the treatment of hemophilia A and B with inhibitors and congenital FVII deficiency. Moreover, the investigational uses of rFVIIa are becoming of interest since it can be used to treat various clinical bleeding conditions. However, there is evidence showing that rFVIIa is a potent procoagulant agent that potentially leads to an increased risk of thrombotic complications. Objectives: To design a new rFVII with lower coagulant activity that could potentially be used as an alternative hemostatic agent aiming to minimize the risk of thrombogenicity. Methods: D60A was introduced into the F7 sequence by polymerase chain reaction-based mutagenesis. Wild type (WT) and D60A were generated in human embryonic kidney 293T cells by stable transfection. FVII coagulant activities were determined by amidolytic cleavage of the FVIIa-specific substrate, 2-step FXa generation, thrombin generation (TG), and clot-based assays. Results: WT and D60A demonstrated similar FVIIa amidolytic activity. However, D60A showed approximately 50% activity on FX activation and significantly longer lag time in the TG assay than that shown by WT. The clotting time produced by D60A spiked in FVII-deficient plasma was significantly prolonged than that of WT. Additionally, the ex vivo plasma half-lives of WT and D60A were comparable. Conclusion: D60A demonstrated lower coagulant activities, most likely due to the weakening of FX binding, leading to impaired FX activation and delayed TG and fibrin formation. Considering that a plasma FVII level of 15% to 25% is adequate for normal hemostasis, D60A is a molecule of interest for future development of an rFVII with a lesser extent of thrombogenicity.

Targeting tissue factor pathway inhibitor with concizumab to improve hemostasis in patients with Glanzmann thrombasthenia: an in vitro study.

BACKGROUND: Glanzmann thrombasthenia (GT) is caused by an inherited defect of platelet αIIbß3 integrin. Concizumab, a monoclonal antibody specific for tissue factor pathway inhibitor, abolishes its anticoagulant effect. OBJECTIVES: To evaluate the in vitro ability of concizumab to improve hemostasis in GT. METHODS: The effects of concizumab were evaluated in whole blood or platelet-rich plasma from GT patients (n = 5-9) using a thrombin generation assay, rotational thromboelastometry (ROTEM), a global fibrinolytic capacity assay, and a flow chamber assay (Total Thrombus formation Analysis System). Washed platelets (WPs) and 20 nM recombinant activated factor VII (rFVIIa) were included for comparison. RESULTS: The lag time in the thrombin generation assay was significantly longer (+85%; P < .0001) in GT patients than in controls. WPs, rFVIIa, and concizumab each significantly improved thrombin generation profiles. The ROTEM clotting time (CT) was significantly longer in GT patients than in controls (677 seconds vs 523 seconds; P = .03). However, CT improved after adding WPs, rFVIIa, or concizumab. Under flow, occlusive thrombi were present in all healthy controls after 10 minutes, whereas platelet-fibrin depositions were not seen in GT patients. Subocclusive or occlusive thrombi formed when GT blood was mixed with WPs, rFVIIa, or concizumab. Clots in GT platelet-rich plasma were more susceptible to fibrinolysis and were improved by WPs, rFVIIa, or concizumab. CONCLUSION: Concizumab enhanced thrombin generation, decreased the ROTEM CT, improved thrombus formation under flow, and reduced clot lysis. Our results demonstrate the potential of concizumab for subcutaneous prophylaxis in GT patients.

Perioperative administration of recombinant activated factor VII in a Glanzmann's thrombasthenia patient with platelet refractoriness: case report.

Glanzmann's Trombasthenia (GT) is a genetic disorder, that develops with a tendency toward bleeding and is characterized by the absence or decrease in platelet aggregation. Surgical bleeding may be difficult to control. Platelet transfusion is the main treatment, albeit refractoriness can occur. We describe the case of a patient with GT and platelet refractoriness, who was submitted to radical prostatectomy and dental extraction. The perioperative treatment with apheresis platelet concentrate and activated recombinant factor seven allowed the procedures to be performed uneventfully. We discuss the complexity of the case and the treatment option.

Acquired hemophilia in a 7-year-old girl successfully treated with recombinant FVIIA and steroids: A case report.

Acquired hemophilia should be evaluated in pediatric patients with bleeding and isolated prolonged aPTT. Immunosuppressive treatment should be initiated even in minor bleedings. Bypassing agents like rFVIIa can be used in children with success.

Risk factors of diffuse alveolar hemorrhage after acute ischemic stroke treated with tissue-type plasminogen activator. The effectiveness of activated recombinant factor VII treatment.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a rare and frequently life-threatening complication of a variety of conditions. DAH may result from coagulation disorders, inhaled toxins, or infections. We report a series of patients who developed DAH after receiving a tissue-type plasminogen activator (tPA) for acute cerebral infarction. We aimed to find risk factors of DAH in patients receiving tPA and the effectiveness of activated recombinant factor VII (rFVIIa) treatment for the same. CASE DESCRIPTION: A total of 1023 acute ischemic stroke (AIS) patients who received tPA in our department from January 2006 to December 2018 were enrolled in this study. Four of the 1023 patients (0.39%) developed DAH. The modified Rankin scale was used to assess clinical severity. Infarction volume was assessed upon follow-up using DWI (diffusion-weighted imaging). Atherothrombotic brain infarction cases were excluded from the study. The age, sex, occlusion site, area of infarction, emphysema, intracranial hemorrhage, and neurological outcomes were analyzed. Patients who developed DAH were more likely to have a history of emphysema. We administered rFVIIa to three DAH patients with good prognosis. CONCLUSION: The inclusion/exclusion criteria of tPA were based on the AHA/ASA Guidelines for the early management of patients with AIS.These patients had no evidence of infections, bronchoscopy, autoimmune diseases, HIV, and transplantations. Our study suggests that systemic administration of rFVIIa for DAH is effective. Emphysema may be a risk factor for the development of DAH following tPA. When we use tPA for emphysema patients, we must be careful about DAH enough.

Life-Threatening Pulmonary Hemorrhage Responds to Recombinant Factor VIIa: A Case Series in South Florida Hospitals.

Intravenous recombinant activated Factor VIIa (rFVIIa) is approved as a hemostatic agent for only a few bleeding disorders. Since the first reported case of off-label use for rFVIIa in 1999, off-label use far exceeds the use for approved conditions. The endobronchial administration of rFVIIa to control alveolar hemorrhage has been published in only a few case reports. Herein we report a case series of endobronchial rFVIIa use for life-threatening pulmonary hemorrhage at two institutions in south Florida.

Successful outcomes of surgery procedures in patient with Glanzmann´s Thrombasthenia

We report a 35-year-old female patient with Glanzmann's thrombasthenia (GT) and severe anemia due to abnormal uterine bleeding secondary to uterine myomatosis. She required several admissions of red blood cells and platelet transfusions. An elective subtotal hysterectomy with salpingo-oophorectomy was proposed and recombinant factor VII was required. Surgical and postoperative outcomes were successful, without surgical complications, bleeding, or hemogram alterations. 4 years later, she required tooth extraction because of periodontal disease and pulp necrosis. In Peru, reports of GT patients requiring major and minor surgical procedures are lacking, given the low disease prevalence and the difficulties related to surgery. The report of these successful cases becomes relevant to continue improving GT management.

Presentamos el caso de una paciente de 35 años con trombastenia de Glanzmann (GT) y anemia severa por sangrado uterino anormal secundario a miomatosis uterina. Requirió varias admisiones de transfusiones de glóbulos rojos y plaquetas. Se propuso histerectomía subtotal electiva con salpingo-ooforectomía y se requirió factor VII recombinante. Los resultados quirúrgicos y postoperatorios fueron exitosos, sin complicaciones quirúrgicas, sangrado ni alteraciones del hemograma. 4 años después, requirió extracción dental por enfermedad periodontal y necrosis pulpar. En Perú faltan reportes de pacientes con GT que requieran procedimientos quirúrgicos mayores y menores, dada la baja prevalencia de la enfermedad y las dificultades relacionadas con la cirugía. El reporte de estos casos de éxito cobra relevancia para seguir mejorando la gestión de GT

Perioperative administration of recombinant activated factor VII in a Glanzmann's thrombasthenia patient with platelet refractoriness: case report

Abstract Glanzmannʼs Trombasthenia (GT) is a genetic disorder, that develops with a tendency toward bleeding and is characterized by the absence or decrease in platelet aggregation. Surgical bleeding may be difficult to control. Platelet transfusion is the main treatment, albeit refractoriness can occur. We describe the case of a patient with GT and platelet refractoriness, who was submitted to radical prostatectomy and dental extraction. The perioperative treatment with apheresis platelet concentrate and activated recombinant factor seven allowed the procedures to be performed uneventfully. We discuss the complexity of the case and the treatment option.

The Effect of Intravenous Administration of Active Recombinant Factor VII on Postoperative Bleeding in Cardiac Valve Reoperations; A Randomized Clinical Trial.

BACKGROUND: Postoperative bleeding after cardiac reoperations is among the most complicating problems, both for the physicians and for the patients. Many modalities have been used to decrease its adverse effects and the need for blood products administration. OBJECTIVES: In a randomized double-blinded clinical trial of redo cardiac valve surgery in adult, the effect of active recombinant factor VII (rFVIIa) on postoperative bleeding was compared with placebo. Chest tube drainage was used for comparison of bleeding between the two groups. PATIENTS AND METHODS: Two groups of 18 patients undergoing redo valve surgeries were treated and compared regarding chest tube drainage, need for blood products, prothrombin time (PT), partial thromboplastin time (PTT), hemoglobin and hematocrit, platelet count, and international normalized ratio (INR) in first 24 hours after surgery. Bleeding was assessed at 3rd, 12th, and 24th hour after operation. In rFVIIa group, 40 µg/kg of AryoSeven was administered before end of surgery and same volume of normal saline was administered as placebo in the control group. RESULTS: Study groups showed no difference regarding baseline variables. Three patients in rFVIIa group (16.67%) and 13 in placebo group (72.23%) received blood products (P < 0.01). Chest tube blood drainage at 24th hour after operation was 315 ± 177 mL in rFVIIa group and 557 ± 168 mL in control group (P = 0.03). At third and 12th hour after operation, the difference was not statistically significant (P = 0.71 and P = 0.22, respectively). Postoperative ICU stay was not different; while extubation was longer in the placebo group (352 ± 57 vs. 287 ± 46 minutes; P = 0.003). CONCLUSIONS: Our study demonstrated the efficacy of rFVIIa in controlling postoperative bleeding in redo cardiac valve surgeries regarding subsequent blood loss and transfusion requirement; however, outcome results remains to be defined.

Successful use of N-acetyl cysteine and activated recombinant factor VII in fulminant hepatic failure and massive bleeding secondary to dengue hemorrhagic fever.

Consensus on management of complicated cases of dengue infection is evolving. Dengue hemorrhagic fever (DHF) occasionally progress to fulminant liver failure with high fatality rate. Inadvertent use of blood products to control massive bleeding in dengue shock syndrome may worsen fluid overload and subsequently the multi-organ dysfunction. We report a case of 37-years-old Sri Lankan man who developed fulminant liver failure and massive bleeding associated with DHF, subsequently recovered completely with supportive measures including administration of N-acetyl cysteine and activated recombinant factor VII. In conclusion, prevention of ischemic injury to liver and adoption of early aggressive supportive measures in complicated cases of dengue hemorrhagic fever is crucial for a favorable outcome. Indications for rFVIIa to arrest uncontrolled internal bleeding and use of NAC in non-acetaminophen-induced acute liver failure in complicated DHF are a platform for discussion.

Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastography.

BACKGROUND: Dabigatran etexilate, a pro-drug of a direct thrombin inhibitor, was approved a few years ago for non-valvular atrial fibrillation and deep venous thrombosis. Rapid monitoring of the dabigatran level is essential in trauma and bleeding patients but the traditional plasma-based assays may not sufficiently display the effect. Furthermore, no antidote exists and reversal of the anticoagulant effect is impossible or difficult. The present study investigated the in vitro effect of dabigatran on whole blood thromboelastography (TEG) and its reversal by recombinant activated factor VII and prothrombin complex concentrate. METHODS: Blood was collected from 10 healthy donors and spiked in vitro with therapeutic doses of dabigatran to a plasma concentration of 200 ng/ml, followed by therapeutic doses of recombinant activated factor VII (corresponding to 100 µg/kg) and prothrombin complex concentrate (corresponding to 50 IE/kg) and evaluated by TEG. RESULTS: Compared to baseline, dabigatran changed all TEG parameters in a hypocoagulable direction corresponding to increased R time and time to maximum rate of thrombus generation, reduced angle, A5, A10, maximum amplitude and maximum rate of thrombin formation. Recombinant activated factor VII had a procoagulant effect on the majority of the investigated TEG parameters when added to dabigatran spiked samples. Prothrombin complex concentrate appeared not to have a procoagulant effect on TEG even when the heparin content in the formulation was neutralized by heparinase. CONCLUSIONS: TEG displays the presence of dabigatran in whole blood in vitro and the anticoagulant effect of dabigatran is partly reversed by spiking with recombinant activated factor VII.

Race against the clock: overcoming challenges in the management of anticoagulant-associated intracerebral hemorrhage.

Patients receiving anticoagulation therapy who present with any type of intracranial hemorrhage--including subdural hematoma, epidural hematoma, subarachnoid hemorrhage, and intracerebral hemorrhage (ICH)--require urgent correction of their coagulopathy to prevent hemorrhage expansion, limit tissue damage, and facilitate surgical intervention as necessary. The focus of this review is acute ICH, but the principles of management for anticoagulation-associated ICH (AAICH) apply to patients with all types of intracranial hemorrhage, whether acute or chronic. A number of therapies--including fresh frozen plasma (FFP), intravenous vitamin K, activated and inactivated prothrombin complex concentrates (PCCs), and recombinant activated factor VII (rFVIIa)--have been used alone or in combination to treat AAICH to reverse anticoagulation, help achieve hemodynamic stability, limit hematoma expansion, and prepare the patient for possible surgical intervention. However, there is a paucity of high-quality data to direct such therapy. The use of 3-factor PCC (activated and inactivated) and rFVIIa to treat AAICH constitutes off-label use of these therapies in the United States. However, in April 2013, the US Food and Drug Administration (FDA) approved Kcentra (a 4-factor PCC) for the urgent reversal of vitamin K antagonist (VKA) anticoagulation in adults with acute major bleeding. Plasma is the only other product approved for this use in the United States. (1) Inconsistent recommendations, significant barriers (e.g., clinician-, therapy-, or logistics-based barriers), and a lack of approved treatment pathways in some institutions can be potential impediments to timely and evidence-based management of AAICH with available therapies. Patient assessment, therapy selection, whether to use a reversal or factor repletion agent alone or in combination with other agents, determination of site-of-care management, eligibility for neurosurgery, and potential hematoma evacuation are the responsibilities of the neurosurgeon, but ultimate success requires a multidisciplinary approach with consultation from the emergency department (ED) physician, pharmacist, hematologist, intensivist, neurologist, and, in some cases, the trauma surgeon.

Use of recombinant activated factor VII for bleeding following resection of mediastinal angiosarcoma.

Sarcomatous lesions of the mediastinum usually present as aggressive and multicentre masses often attached to adjoining structures including heart and lungs. A forty one year male diagnosed with sarcomatous lesion in mediastinum presented for biopsy through midsternotomy later confirmed as angiosarcoma on histopathology. Patient bled excessively after surgery and required reopening of the chest. However, bleeding could not be controlled with reopening, blood products and packing of the mediastinal cavity. Bleeding could only be controlled by using recombinant activated factor VII as rescue therapy without any adverse effects.

The role of recombinant activated factor VII in cardiac surgery.

Recombinant factor VIIa may reduce surgical blood loss and transfusion of blood products in cardiac surgery. However, the true risks of its use in this setting remains to be elucidated, especially when it is administered with other potent pro-haemostatic agents. We reviewed the recent literature on this topic and suggest that the off label use of recombinant factor VIIa is likely to continue. It is our institutional practice to use it in the operating room at a dose of 90 mcg/Kg to ensure there is no obvious correctable surgical source of blood loss, and to be certain that bleeding has stopped before the chest is closed.