Recombinant FVIIa

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...

INTRODUCTION: Recent technological innovations in haemophilia have advanced at an astounding pace, including gene therapy programmes and bioengineered molecules for prophylaxis, products that reduce treatment burden through half-life extension, unique mechanisms of action, and subcutaneous administration. Additional technological advancements have emerged that are anticipated to further transform haemophilia care. AIM: Review new and emerging haemophilia therapies, including replacement and bypassing products, digital applications, utilisation of big data, and personalised medicine...

INTRODUCTION: Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS: Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs)...

Background and objective Acquired hemophilia A (AHA) is an uncommon autoimmune bleeding disorder caused by the formation of neutralizing antibodies against endogenous factor VIII (FVIII). Delays between the onset of symptoms and the correct diagnosis of the condition lead to poor outcomes and a higher mortality rate. In this study, we aimed to analyze the impact of delays in diagnosis on AHA patients. Methods We conducted a retrospective study at a single hospital system between March 1, 2010, and January 17, 2017, which included six patients meeting the criteria for AHA diagnosis...

Acquired hemophilia A (AHA) is a rare disease with a prevalence in Europe of 1.5 per million. This diagnosis is significantly delayed in about one-third of all cases, leading to deferred treatment. The main signs of AHA are spontaneous bleeding seen in about two-thirds of all patients. AHA can be lethal in 20% of all symptomatic cases. This patient population's main standard laboratory finding is a prolonged aPTT (activated prothrombin Time) with otherwise normal coagulation results. In addition, antibodies against FVIII (in Bethesda Units) and a quantitative reduction of FVIII activity are necessary to confirm AHA...

Background: Patients with hemophilia have deficiencies in intrinsic coagulation factors and can develop inhibitors that limit the effectiveness of replacement coagulation factors. Marstacimab, a human monoclonal antibody, binds and inhibits the human tissue factor pathway inhibitor. Marstacimab is currently under development as a potential prophylactic treatment to prevent bleeding episodes in patients with hemophilia A and B. Objective: To assess the effects of marstacimab alone or in combination with the bypassing agent recombinant factor FVIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC) on thrombin generation and bleeding...

BACKGROUND: The regulation of factor X (FX) is critical to maintain the balance between blood coagulation and fluidity. OBJECTIVES: To functionally characterize the role of the FX autolysis loop in the regulation of the zymogen and active form of FX. METHODS: We introduced novel N-linked glycosylations on the surface-exposed loop spanning residues 143-150 (chymotrypsin numbering) of FX. The activity and inhibition of recombinant FX variants was quantified in pure component assays...

INTRODUCTION: Since the approval of emicizumab, a bispecific, factor VIII-mimetic antibody, for use in persons with congenital haemophilia A in 2018, there have been increasing case reports and case series of off-label use of emicizumab in other bleeding disorders, including acquired haemophilia A (AHA) and von Willebrand disease (VWD). AIM: We conducted a scoping review on the use of emicizumab in AHA and VWD, focusing on the clinical presentation and outcomes...

Hemorrhage in patients with hematologic malignancies is often difficult to manage as many of these patients also have coagulopathy and thrombocytopenia of varying severity. Recombinant factor VIIa is a FDA-approved agent for management of bleeding in hemophilia patients with inhibitors. Use of recombinant FVIIa has also been used as a last resort in various clinical settings such as trauma, alveolar hemorrhage, gastrointestinal bleeding, and intracranial hemorrhage for control of bleeding with variable outcomes...

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...

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...

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A. INTRODUCTION: Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. This is then followed by eradication of the inhibitor with immunosuppression which typically includes a corticosteroid backbone...

BACKGROUND: Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. OBJECTIVES: To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. METHODS: This multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor...

Procoagulant activity of tissue factor (TF) in response to injury or inflammation is accompanied with cellular signals which determine the fate of cells. However, to prevent excessive signalling, TF is rapidly dissipated through release into microvesicles, and/or endocytosis. To elucidate the mechanism by which TF signalling may become moderated on the surface of cells, the associations of TF, fVII/fVIIa, PAR2 and caveolin-1 on MDA-MB-231, BxPC-3 and 786-O cells were examined and compared to that in cells lacking either fVII/fVIIa or TF...

Background: Traumatic injury and the associated acute bleeding are leading causes of death in people aged 1 to 44 years. Acute bleeding in pathological and surgical settings also represents a significant burden to the society. Yet there are no approved hemostatic drugs currently available. While clinically proven as an effective pro-coagulant, activated factor VII (FVIIa) use in acute bleeding has been hampered by unwanted thromboembolic events. Enhancing the ability of FVIIa to quickly stop a bleed and clear rapidly from circulation may yield an ideal molecule suitable for use in patients with acute bleeding...

BACKGROUND: Coronavirus-2 (SARS-CoV-2) infection causes an acute respiratory syndrome accompanied by multi-organ damage that implicates a prothrombotic state leading to widespread microvascular clots. The causes of such coagulation abnormalities are unknown. The receptor tissue factor, also known as CD142, is often associated with cell-released extracellular vesicles (EV). In this study, we aimed to characterize surface antigens profile of circulating EV in COVID-19 patients and their potential implication as procoagulant agents...

As perioperative bleeding continues to be a major source of morbidity and mortality in cardiac surgery, the search continues for an ideal hemostatic agent for use in this patient population. Transfusion of blood products has been associated both with increased costs and risks, such as infection, prolonged mechanical ventilation, increased length of stay, and decreased survival. Recombinant-activated factor VII (rFVIIa) first was approved for the US market in 1999 and since that time has been used in a variety of clinical settings...

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...

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...

Clinical parameters have been extensively studied in factor (F) VII deficiency, but the knowledge of molecular mechanisms of this disease is scarce. We report on three probands with intracranial bleeds at early age, one of which had concomitant high titer of FVII inhibitor. The aim of the present study was to identify the causative mutations and to elucidate the underlying molecular mechanisms. All nine F7 exons were sequenced in the probands and the closest family members. A homozygous deletion in exon 1, leading to a frame shift and generation of a premature stop codon (p...