RARE DISEASE
Acquired hemophilia B
Acquired hemophilia B
Acquired hemophilia B
Synonyms: AHB, Acquired F9 deficiency, Acquired factor IX deficiency
Synonyms: AHB, Acquired F9 deficiency, Acquired factor IX deficiency
Synonyms: AHB, Acquired F9 deficiency, Acquired factor IX deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Acquired hemophilia B (AHB) is a rare autoimmune bleeding disorder caused by autoantibodies (inhibitors) targeting factor IX, leading to impaired clotting. It occurs spontaneously, often in older adults or postpartum women, without prior personal/family bleeding history. Diagnosis involves prolonged activated partial thromboplastin time (aPTT) and low factor IX activity with inhibitor detection. Mortality rates reach 21%, primarily from bleeding complications [3][6][16].
Therapies
Acute bleeding: Bypassing agents (recombinant FVIIa, activated prothrombin complex concentrate) [3][6]
Inhibitor eradication: Immunosuppression (corticosteroids ± cyclophosphamide; rituximab for refractory cases) [3][16]
Prophylaxis: Avoided unless recurrent bleeds; managed in specialized centers [3][16]
Categories: rare hematological diseases
Research Papers
72 drug discovery papers about Acquired hemophilia B, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
72 drug discovery papers about Acquired hemophilia B, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-20 | Screening chemical libraries for the development of oral treatments in bleeding disorders
• A high-throughput screening of 2300 chemical compounds allowed to identify adapalene as a procoagulant on severe hemophilia A plasma. • The mechanism of action of adapalene involves Factor XII activation. Hemophilia is a rare bleeding disorder due to Factor VIII (FVIII) or Factor IX (FIX) deficiency respectively involved in hemophilia A (HA) or B (HB). Treatment has long relied on invasive intravenous infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for hemophiliacs. Such an oral procoagulant could benefit to other inherited and acquired bleeding disorders, as well as anticoagulants-induced bleedings. To find chemical compounds that could become potential future orally-administered procoagulants, we designed a hierarchical high-throughput screening protocol combining two successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened three chemical collections totalizing more than 2300 chemical compounds; we identified adapalene, a commercialized anti-acneic compound (Differin®) which is strongly hydrophobic. In order to design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and three of them, with similar procoagulant activities in FVIII deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies allow to conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of Factor XII.
2014-09-29 | Use of prothrombin complex concentrates: 4-year experience of a national aeromedical retrieval service servicing remote and rural areas.
Prothrombin complex concentrates (PCCs) are recommended as first-line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients. We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards. During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs. In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care.
2012-11-09 | Heparin-induced effects of prothrombin complex concentrates in thromboelastometry.
Prothrombin complex concentrates (PCC) are currently used to treat congenital or acquired coagulation factor deficiency. In case of serious bleeding caused by new oral anticoagulant agents, reversing treatment with PCC is under debate. PCC preparations mostly contain heparin to prevent thromboembolic events. In factor VIII and IX deficient plasma, Takeyama et al. observed in vitro a heparin effect at appropriate concentrations of PCCs. The aim of the present experiment was to investigate the heparin effect of four factor-PCC at clinically relevant concentrations in whole blood. In an in vitro experiment, we compared the PCC preparation used in the experiments of Takeyama with a high heparin content to a new heparin-free PCC preparation. After ethics committee approval and written informed consent, the citrated whole blood was obtained from ten healthy volunteers. We tested heparin-containing Prothromplex(®) and heparin-free Cofact(®) at concentrations of 0.31, 0.63, and 1.25 IU/ml. Protamine was added to another set of samples (1:1 heparin:protamine). We used the NATEM test in the rotational thromboelastometer ROTEM(®). In the heparin PCC preparation, we observed a significant (p < 0.001) concentration-dependent prolongation in CT and CFT, even at the lowest concentration. MCF was also significantly reduced. The heparin effect was reversible by protamine. The heparin-free PCC did not affect the onset of coagulation. The interpretation of the alpha-angle showed no increased thrombus formation in heparin-free PCC preparation. Our results extend the report of Takeyama et al. At clinically relevant PCC concentrations, the heparin effect was significant in thromboelastometry. The heparin content of PCCs should be considered in clinical routine.
2012-02-07 | [Acquired haemophilia B: a case report and literature review].
Acquired haemophilia is a rare disease; it occurs most frequently in elderly patients. The majority of cases are due to autoantibodies to factor VIII, which deplete circulating factor VIII or acquired haemophilia A. Only few cases of acquired haemophilia B are reported until today. We report a case of a 7-year-old girl with no past medical history of bleeding disorder and who present an extensive haematoma in the left calf. The diagnosis was established by the demonstration of an isolated prolongation of the activated partial thromboplastin time (APTT) with a reduced factor IX level and evidence of factor IX inhibitor activity to 2 Bethesda Unit (2UB). Diagnosis of acquired haemophilia B confirmed, patient received recombinant factor VIIa and corticosteroid treatment. Bleeding symptoms had completely disappeared and coagulation tests become normal. In conclusion, if bleeding symptoms are associated with unexplained prolongation of APTT, an inhibitor against factor must be searched for not missing an acquired coagulation disease.
2011-05-31 | Factor VIII and IX deficiencies related to acquired inhibitors in a patient with chronic hepatitis C virus infection receiving treatment with pegylated interferon plus ribavirin.
The development of clotting factor inhibitor autoantibodies is rarely observed, but can result in a potentially life-threatening haemorrhagic disorder. These acquired inhibitors are most frequently against factor VIII (FVIII), whilst the detection of inhibitors against other clotting factors is rarer. Inhibitors against FVIII and FIX are mostly observed in patients with classical hereditary haemophilia after receiving factor replacement therapy. We report a rare case of acquired FVIII and factor IX (FIX) inhibitors in a single, non-haemophilic patient with chronic hepatitis C virus (HCV) infection who was receiving antiviral treatment with pegylated interferon plus ribavirin. The FVIII and FIX activities were <1% and high titres of inhibitors autoantibodies were found in his serum samples. After achieving a sustained virological response, combined immunosuppression with oral corticosteroids (prednisone) and azathioprine was introduced, eradicating the inhibitory autoantibodies. The development of these inhibitors in association with antiviral therapy for chronic hepatitis C is poorly understood, and particular attention must be given to HCV-infected patients with worsening coagulopathy, particularly if coexistent with treatment related thrombocytopenia.
antibodies
2025-08-05 | PO27 | B-cell lymphoproliferative disorder and acquired coagulopathy: an insidious link
Background: Acquired coagulation factor inhibitors are autoantibodies that may develop in individuals with autoimmune or neoplastic disorders and should be assessed in patients without personal or familiar history of bleeding disorders. These inhibitors most commonly target factor VIII (FVIII) or von Willebrand factor (VWF), resulting in acquired haemophilia A or acquired von Willebrand disease, respectively and may occasionally interfere with the normal activity of other coagulation factors. Case Report: An 81-year-old female presented with recurrent episodes of anterior epistaxis and ecchymoses, without history of personal bleeding disorders. Laboratory testing revealed deficiencies in vitamin K–dependent factors (except for factor IX) in the absence of liver dysfunction or other known causes of coagulopathy, raising suspicion of an acquired haemorrhagic disorder. Past medical history included an indolent B-cell lymphoproliferative disorder, under haematological follow-up and arterial hypertension. Clinically, the patient exhibited persistent mucocutaneous bleeding associated with progressive anaemia and transient memory deficits. Due to suspected central nervous system involvement, an MRI was performed, revealing a small haemorrhagic area in the fornix of the limbic system. At the admission, coagulation studies confirmed markedly abnormal coagulation parameters: PT/INR 5.36 and aPTT 1.56. The mixing test showed suboptimal correction. The laboratory evaluation revealed: Factor IX 171%, Factor II 5%, Factor VII 17%, Factor X 7%, Protein S 51%, and Protein C 24%. Mixing studies for Factors II and VII demonstrated suboptimal correction, suggesting the presence of inhibitors. Lupus anticoagulant and antiphospholipid antibodies were negative. According to these results, we hypnotized the presence of a poly-specific serum para-protein interfering with clotting factors. Intravenous vitamin K (Konakion 10 mg) induced a not significant resolution of PT prolongation followed by a rebound increase to 4.66 and 5.27. PIVKA-II levels were 41 AU/mL (negative), supporting the lack of a functional vitamin K deficiency. Immunosuppressive steroid therapy with prednisone was started at the time of admission. Given the known lymphoproliferative disorder, the possibility of a neoplastic trigger for the coagulation abnormality was considered. Flow cytometry confirmed the presence of a B-cell clone expressing CD20, with a 2% blast count. After 15 days of steroid therapy without clinical improvement, a pharmacokinetic assessment was conducted following the administration of a 4-factor prothrombin complex concentrate (PCC). Factor levels were measured at baseline and several time points post-infusion (30 min, 1h, 2h, 4h, 12h, 24h). A marked decline in circulating coagulation factors was noted after 4 hours, with the greatest reduction observed for Factor II, suggesting preferential inhibitory activity against this factor, likely due to the presence of a neoplastic paraprotein. Therapy with rituximab (anti-CD20 monoclonal antibody) was then introduced at the standard dose of 375 mg/m² weekly for four weeks with complete normalisation of coagulation. Conclusions: This case highlights the diagnostic and therapeutic challenges posed by rare coagulation inhibitors. The successful use of rituximab underscores the relevance of B-cell–directed immunosuppression in managing such complex cases, particularly in the context of clonal B-cell disorders.
2020-09-23 | Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine.
Patients with haemophilia A (HA) or B (HB) experience spontaneous limb- or life-threatening bleedings which are prevented by regular prophylactic intravenous infusions of the deficient coagulation factor (FVIII or FIX). Prophylaxis with subcutaneous long-acting non-factor products that improve in vivo thrombin generation is now under intensive investigation (concizumab, fitusiran) or successfully employed (emicizumab) in haemophilia patients. Both haemophilia patients with/without inhibitors take advantage of non-factor products employed alone. In those who also need bypassing agents (or FVIII concentrates) for breakthrough bleeds, thromboembolic events and/or thrombotic microangiopathy may occur. By enhancing thrombin generation, prothrombotic mutations co-segregating with FVIII/FIX gene mutations may trigger thrombotic episodes in HA patients carrying acquired thrombogenic factors (e.g. venous catheters). A thorough knowledge of individual needs increasingly contributed to improve comprehensive care and personalize treatments in haemophilia. Integrating genomics, lifestyle and environmental data is expected to be key to: 1) identify which haemophilia patients are less likely to benefit from a given intervention; 2) define optimal dosing and scheduling of bypassing agents (or FVIII) to employ in combination with non-factor products; 3) establish tests to monitor in vivo thrombin generation; 4) improve communication and deliver results to individuals. As individual outcomes will be improved and the risk of adverse events minimized, non-factor products will come into wider use within the haemophilia community, and patients will hopefully have no more risks of breakthrough bleeds. The risks of a normal life for a "former haemophilia patient" is likely to change the treatment landscape and the structure of haemophilia Centers.
2020-05-14 | [Acquired autoimmune haemophilia: Where is the place of rituximab in the treatment strategy? Reflection from a monocentric series of 8 patients and literature review].
Autoimmune acquired haemophilia is a rare autoimmune disease. The purpose of immunosuppressive therapy is to stop the production of autoantibodies that inhibit clotting factors VIII or IX. A corticosteroids-cyclophosphamide combination is recommanded as first-line therapy. From our experience at the University Hospital of Nîmes, we discuss the place of rituximab in the therapeutic arsenal. We report a monocentric observational retrospective study. Our data are discussed in light of literature data, in particular cohorts EACH2 and SACHA. Eight patients (7 with FVIII anibodies) were consecutively included from 2005. The average age was 68.5 years with a male predominance (62.5%). Bleeding manifestations were usually spontaneous and superficial. A pathology, mostly autoimmune or neoplastic, was associated in 5/8 patients. A "by-pass" haemostatic treatment was prescribed for 3/8 patients. Rituximab was prescribed for 5/8 patients, three times as first-line therapy, and always associated with corticosteroids. Three patients received a cyclophosphamid/cortisone combination, two were treated exclusively with oral corticosteroids. Remission was obtained in all patients, without subsequent relapse. The average time to obtain remission under rituximab (after the first injection) was 32.5 days (10-143). The results observed in our series of patients are consistent with the data from the literature. Rituximab appears to be an effective and well-tolerated treatment for autoimmune acquired haemophilia. However, its place remains to be specified.
2011-03-31 | Proteolytic antibodies activate factor IX in patients with acquired hemophilia.
Acquired hemophilia is a rare bleeding disorder characterized by the spontaneous occurrence of inhibitory antibodies against endogenous factor VIII (FVIII). IgG from some patients with acquired hemophilia hydrolyze FVIII. Because of the complex etiology of the disease, no clinical parameter, including the presence of FVIII-hydrolyzing IgG, has been associated with patient's survival or death. Here, we demonstrate the presence of anti-FIX antibodies in acquired hemophilia patients. IgG from some patients were found to hydrolyze FIX. In most cases, IgG-mediated FIX-hydrolysis resulted in FIX activation. IgG-mediated hydrolysis of FIX thus led to the significant generation of activated FIX in 25 of 65 patients. Based on the estimated kinetic parameters, patients' IgG activated up to 0.3nM FIX in 24 hours, an amount that restored thrombin generation in vitro provided the presence of more than or equal to 3% residual FVIII activity in plasma. This work identifies proteolytic IgG as novel molecules able to activate FIX under pathologic conditions. IgG-mediated FIX activation is a prevalent phenomenon among acquired hemophilia patients. The presence of FIX-activating IgG may partly compensate for the antibody-mediated inhibition of endogenous FVIII in restoring thrombin generation. This clinical trial was registered at www.clinicaltrials.gov as #NCT00213473.
1986-04-10 | HTLV III antibodies and immunological alterations in hemophilia patients.
The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.
gene therapies
2026-06-21 | Development of an Agent-Based Model to Investigate Durability of Factor IX Activity in Hemophilia B Patients Treated With Etranacogene Dezaparvovec.
Many currently approved gene therapies use adeno-associated virus (AAV) to deliver DNA sequences encoding protein(s)-of-interest into cells. The AAV viral genome forms stable, circular DNA structures called episomes after entering the nuclei. Therapeutic proteins are then generated in vivo from transcription and translation of these episomes, and long-term durability thus depends on episome stability. Prior modeling work has utilized differential equation-based models to characterize AAV uptake and subsequent protein production. However, episome loss associated with target cell turnover is poorly described with these models. Here, an agent-based model (ABM) to overcome this shortcoming is developed. The liver was used as the example organ as it is known to be self-renewing and has been a common target for gene therapies. In this model, each hepatocyte is an agent, capable of division and death. When transduced, these agents acquire and carry episomes. During cell division, episomes are passed from mother to daughter cells. All episomes are presumed lost when transduced cells die. The ABM was applied to etranacogene dezaparvovec (formerly AMT-061 or CSL222), a liver-targeting gene therapy for hemophilia B consisting of AAV serotype 5 particles encoding a transgene for the Padua variant (R338L) of coagulation factor IX (FIX). ABM-simulated FIX activity in patients receiving this therapy was consistent with clinical observations over more than 2 years following treatment. This ABM was then used to generate 20-year predictions and explore biological mechanisms underlying long-term durability. The ABM framework and approach should be applicable to investigating durability of other AAV-based gene therapies.
2024-09-13 | Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B
Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.
2023-12-15 | HEMOPHILIA: DIAGNOSIS AND INNOVATIVE MANAGEMENT.
Hemophilia is an acquired,X-linked,passive disorder caused by an insufficiency of utilitarian plasma clotting factor VIII (FVIII). In a critical number of cases, the disorder results from a novo mutation. It rarely manifests as an acquired autoimmune process.Research facility thinks about for suspected hemophilia include a total blood cell tally,coagulation ponders, and an FVIII assay. In patients with an established diagnosis of hemophilia, periodic research facility evaluations include screening for the presence of FVIII inhibitors and screening for transfusion-related or transmissible illnesses such as hepatitis and HIV contamination. Estimation of FVIII levels is critical for observing FVIII substitution treatment. Treatment of hemophilia includes prophylaxis, treatment of bleeding episodes, and induction of immune tolerance.Intended for the treatment and rehabilitation of the patients who are taking factor inhibitors and patients have hemophilic synovitis. Treatment for hemophiliacs should ideally be provided by a Hemophilia Day Care center.We discuss innovative management for the prevention of hemophilia through gene therapy,non-replacement therapy,EHL recombinant concentration,etc.we discuss the data from our studies and emerging results from other gene therapy trials in both hemophilia A and B. This analysis will provide evidence and information on the feasibility and data quality/completeness of the hemophilia database to assess the impact of innovative management on hemophilia outcomes in developing countries.We used a statistical method to analyze the data of adult and pediatric patients who come to hemophilia day care center for taking treatment.The data analysis was performed by the data collected monthly at the hemophilia day care center.
2021-01-04 | Gene therapy for hemophilias: the end of phenotypic testing or the start of a new era?
: Hemophilia comprises two distinct genetic disorders caused by missing or defective clotting factor VIII (hemophilia A) or clotting factor IX (hemophilia B). The management of these conditions has been for long based on replacement therapies, but emerging evidence garnered from recent landmark studies suggests that a promising avenue toward routine use of gene therapy is clearly progressing forward, thus generating unavoidable consequences on laboratory hemostasis, especially as pertaining to phenotypic testing. Although it seems likely that widespread use of gene therapy will be associated with a relative decrease of hemostasis tests requests in this patient population due to the relatively stable effect of transgene delivery and persistent production of endogenous clotting factor, some important aspects persuade us that conventional laboratory diagnostics, especially encompassing activated partial thromboplastin time, as well as one-stage and two-stage clotting factor assays, will not be completely voided in the gene therapy era. In particular, phenotypic testing will remain essential for excluding acquired or sporadic cases of hemophilia, for identifying and titrating factor inhibitors, as well as for defining and monitoring the long-term therapeutic effectiveness of gene transfection in hemophiliacs.
2017-12-25 | Baboon envelope pseudotyped lentiviral vectors efficiently transduce human B cells and allow active factor IX B cell secretion in vivo in NOD/SCIDγc-/- mice.
Essentials B cells are attractive targets for gene therapy and particularly interesting for immunotherapy. A baboon envelope pseudotyped lentiviral vector (BaEV-LV) was tested for B-cell transduction. BaEV-LVs transduced mature and plasma human B cells with very high efficacy. BaEV-LVs allowed secretion of functional factor IX from B cells at therapeutic levels in vivo. Background B cells are attractive targets for gene therapy for diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen-presenting cells. Objective Evaluation of human B cells for secretion of clotting factors such as factor IX (FIX) as a possible treatment for hemophilia. Methods We tested here for the first time our newly developed baboon envelope (BaEV) pseudotyped lentiviral vectors (LVs) for human (h) B-cell transduction following their adaptive transfer into an NOD/SCIDγc-/- (NSG) mouse. Results Upon B-cell receptor stimulation, BaEV-LVs transduced up to 80% of hB cells, whereas vesicular stomatitis virus G protein VSV-G-LV only reached 5%. Remarkably, BaEVTR-LVs permitted efficient transduction of 20% of resting naive and 40% of resting memory B cells. Importantly, BaEV-LVs reached up to 100% transduction of human plasmocytes ex vivo. Adoptive transfer of BaEV-LV-transduced mature B cells into NOD/SCID/γc-/- (NSG) [non-obese diabetic (NOD), severe combined immuno-deficiency (SCID)] mice allowed differentiation into plasmablasts and plasma B cells, confirming a sustained high-level gene marking in vivo. As proof of principle, we assessed BaEV-LV for transfer of human factor IX (hFIX) into B cells. BaEV-LVs encoding FIX efficiently transduced hB cells and their transfer into NSG mice demonstrated for the first time secretion of functional hFIX from hB cells at therapeutic levels in vivo. Conclusions The BaEV-LVs might represent a valuable tool for therapeutic protein secretion from autologous B cells in vivo in the treatment of hemophilia and other acquired or inherited diseases.
proteins
2025-12-22 | A Novel Framework for Factor Replacement in Patients Undergoing Liver Transplantation for End Stage Liver Disease
Background The management of coagulopathy and rebalanced hemostasis in end-stage cirrhosis is challenging. Additionally, a certain subset of patients presenting for transplant may have additional acquired or inherited coagulation disorders in addition to liver disease. In patients with these coagulation disorders, there is no updated guidance for isolated factor replacement. Inspired by a case at our institution, we conducted a pilot study to propose a framework to develop a goal-directed dosing strategy for factor repletion in patients presenting for liver transplantation. Methods To determine the level of coagulation factors and the between and within patient variation, factors FVII, FIX, FX, Antithrombin (AT), Protein C (PC), and Protein S (PS) were measured in 41 patients with end stage liver disease and undergoing liver transplantation. Results Coagulation factor data was collected from forty-one patients presenting for liver transplantation. The median level of all measured coagulation factors was below 80% (range 26–76%). The median levels varied widely in studied population (2.1-fold median interquartile range). Notably, measured levels of FIX were strongly correlated with other factors in individual patients: FIX versus FVII (R = 0.81, p < 0.001), FX (R = 0.74, p < 0.001), AT (R = 0.77, p < 0.001), and Protein C (R = 0.86, p < 0.001). Discussion Considering that the median levels were below 80%, for all factors, that levels varied widely among patients, and that levels were highly intercorrelated in an individual patient, it seems appropriate to propose and alternative and empiric target when substituting FIX in patients with hemophilia B before undergoing liver transplantation. We propose the average level of a set of highly inter-correlated coagulation factors as an empiric target when determining goal level for factor repletion.
2025-04-07 | Twenty years of the four-factor prothrombin complex concentrate Octaplex/Balfaxar: A narrative review.
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4F-PCC beyond its approved indications.
2005-03-07 | Activated prothrombin complex concentrate (FEIBA) treatment during surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience.
Non-activated and activated prothrombin complex concentrates have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 15 minor and six major surgical and invasive diagnostic or therapeutic procedures in eight inhibitor patients with congenital haemophilia A and in two patients with acquired haemophilia. Administration of a loading dose of 100 U kg(-1) of FEIBA followed by 200 U kg (-1) day(-1) in three doses every 8 h for 3 days and then tapering the daily dose to 150-100 U kg(-1), resulted in no severe or unexpected bleeding complications. One adverse event was observed. A 69-year-old man suffered a myocardial infarction the third postoperative day following sigmoidectomy. He was managed safely with opiate analgesia, nitrates and diuretics and the continued use of FEIBA.
small molecules
2026-01-20 | Screening chemical libraries for the development of oral treatments in bleeding disorders
• A high-throughput screening of 2300 chemical compounds allowed to identify adapalene as a procoagulant on severe hemophilia A plasma. • The mechanism of action of adapalene involves Factor XII activation. Hemophilia is a rare bleeding disorder due to Factor VIII (FVIII) or Factor IX (FIX) deficiency respectively involved in hemophilia A (HA) or B (HB). Treatment has long relied on invasive intravenous infusions of the missing factor for prophylaxis or bleeding treatments. Despite significant progress in patient care, there is still no oral procoagulant drug available for hemophiliacs. Such an oral procoagulant could benefit to other inherited and acquired bleeding disorders, as well as anticoagulants-induced bleedings. To find chemical compounds that could become potential future orally-administered procoagulants, we designed a hierarchical high-throughput screening protocol combining two successive screening filters: a miniaturized fibrin formation assay, followed by a thrombin generation assay, both on severe HA plasma. We screened three chemical collections totalizing more than 2300 chemical compounds; we identified adapalene, a commercialized anti-acneic compound (Differin®) which is strongly hydrophobic. In order to design a drug that could be orally administered, we developed a series of chemical analogs of adapalene, and three of them, with similar procoagulant activities in FVIII deficient plasma, showed improved solubilities. The mechanism of action was thoroughly investigated by a series of thrombin generation and enzymatic assays. These studies allow to conclude that the procoagulant activity of the chemical compounds in FVIII-deficient plasma is due to the activation of Factor XII.
2014-09-29 | Use of prothrombin complex concentrates: 4-year experience of a national aeromedical retrieval service servicing remote and rural areas.
Prothrombin complex concentrates (PCCs) are recommended as first-line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients. We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards. During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs. In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care.
2012-11-09 | Heparin-induced effects of prothrombin complex concentrates in thromboelastometry.
Prothrombin complex concentrates (PCC) are currently used to treat congenital or acquired coagulation factor deficiency. In case of serious bleeding caused by new oral anticoagulant agents, reversing treatment with PCC is under debate. PCC preparations mostly contain heparin to prevent thromboembolic events. In factor VIII and IX deficient plasma, Takeyama et al. observed in vitro a heparin effect at appropriate concentrations of PCCs. The aim of the present experiment was to investigate the heparin effect of four factor-PCC at clinically relevant concentrations in whole blood. In an in vitro experiment, we compared the PCC preparation used in the experiments of Takeyama with a high heparin content to a new heparin-free PCC preparation. After ethics committee approval and written informed consent, the citrated whole blood was obtained from ten healthy volunteers. We tested heparin-containing Prothromplex(®) and heparin-free Cofact(®) at concentrations of 0.31, 0.63, and 1.25 IU/ml. Protamine was added to another set of samples (1:1 heparin:protamine). We used the NATEM test in the rotational thromboelastometer ROTEM(®). In the heparin PCC preparation, we observed a significant (p < 0.001) concentration-dependent prolongation in CT and CFT, even at the lowest concentration. MCF was also significantly reduced. The heparin effect was reversible by protamine. The heparin-free PCC did not affect the onset of coagulation. The interpretation of the alpha-angle showed no increased thrombus formation in heparin-free PCC preparation. Our results extend the report of Takeyama et al. At clinically relevant PCC concentrations, the heparin effect was significant in thromboelastometry. The heparin content of PCCs should be considered in clinical routine.
2012-02-07 | [Acquired haemophilia B: a case report and literature review].
Acquired haemophilia is a rare disease; it occurs most frequently in elderly patients. The majority of cases are due to autoantibodies to factor VIII, which deplete circulating factor VIII or acquired haemophilia A. Only few cases of acquired haemophilia B are reported until today. We report a case of a 7-year-old girl with no past medical history of bleeding disorder and who present an extensive haematoma in the left calf. The diagnosis was established by the demonstration of an isolated prolongation of the activated partial thromboplastin time (APTT) with a reduced factor IX level and evidence of factor IX inhibitor activity to 2 Bethesda Unit (2UB). Diagnosis of acquired haemophilia B confirmed, patient received recombinant factor VIIa and corticosteroid treatment. Bleeding symptoms had completely disappeared and coagulation tests become normal. In conclusion, if bleeding symptoms are associated with unexplained prolongation of APTT, an inhibitor against factor must be searched for not missing an acquired coagulation disease.
2011-05-31 | Factor VIII and IX deficiencies related to acquired inhibitors in a patient with chronic hepatitis C virus infection receiving treatment with pegylated interferon plus ribavirin.
The development of clotting factor inhibitor autoantibodies is rarely observed, but can result in a potentially life-threatening haemorrhagic disorder. These acquired inhibitors are most frequently against factor VIII (FVIII), whilst the detection of inhibitors against other clotting factors is rarer. Inhibitors against FVIII and FIX are mostly observed in patients with classical hereditary haemophilia after receiving factor replacement therapy. We report a rare case of acquired FVIII and factor IX (FIX) inhibitors in a single, non-haemophilic patient with chronic hepatitis C virus (HCV) infection who was receiving antiviral treatment with pegylated interferon plus ribavirin. The FVIII and FIX activities were <1% and high titres of inhibitors autoantibodies were found in his serum samples. After achieving a sustained virological response, combined immunosuppression with oral corticosteroids (prednisone) and azathioprine was introduced, eradicating the inhibitory autoantibodies. The development of these inhibitors in association with antiviral therapy for chronic hepatitis C is poorly understood, and particular attention must be given to HCV-infected patients with worsening coagulopathy, particularly if coexistent with treatment related thrombocytopenia.
antibodies
2025-08-05 | PO27 | B-cell lymphoproliferative disorder and acquired coagulopathy: an insidious link
Background: Acquired coagulation factor inhibitors are autoantibodies that may develop in individuals with autoimmune or neoplastic disorders and should be assessed in patients without personal or familiar history of bleeding disorders. These inhibitors most commonly target factor VIII (FVIII) or von Willebrand factor (VWF), resulting in acquired haemophilia A or acquired von Willebrand disease, respectively and may occasionally interfere with the normal activity of other coagulation factors. Case Report: An 81-year-old female presented with recurrent episodes of anterior epistaxis and ecchymoses, without history of personal bleeding disorders. Laboratory testing revealed deficiencies in vitamin K–dependent factors (except for factor IX) in the absence of liver dysfunction or other known causes of coagulopathy, raising suspicion of an acquired haemorrhagic disorder. Past medical history included an indolent B-cell lymphoproliferative disorder, under haematological follow-up and arterial hypertension. Clinically, the patient exhibited persistent mucocutaneous bleeding associated with progressive anaemia and transient memory deficits. Due to suspected central nervous system involvement, an MRI was performed, revealing a small haemorrhagic area in the fornix of the limbic system. At the admission, coagulation studies confirmed markedly abnormal coagulation parameters: PT/INR 5.36 and aPTT 1.56. The mixing test showed suboptimal correction. The laboratory evaluation revealed: Factor IX 171%, Factor II 5%, Factor VII 17%, Factor X 7%, Protein S 51%, and Protein C 24%. Mixing studies for Factors II and VII demonstrated suboptimal correction, suggesting the presence of inhibitors. Lupus anticoagulant and antiphospholipid antibodies were negative. According to these results, we hypnotized the presence of a poly-specific serum para-protein interfering with clotting factors. Intravenous vitamin K (Konakion 10 mg) induced a not significant resolution of PT prolongation followed by a rebound increase to 4.66 and 5.27. PIVKA-II levels were 41 AU/mL (negative), supporting the lack of a functional vitamin K deficiency. Immunosuppressive steroid therapy with prednisone was started at the time of admission. Given the known lymphoproliferative disorder, the possibility of a neoplastic trigger for the coagulation abnormality was considered. Flow cytometry confirmed the presence of a B-cell clone expressing CD20, with a 2% blast count. After 15 days of steroid therapy without clinical improvement, a pharmacokinetic assessment was conducted following the administration of a 4-factor prothrombin complex concentrate (PCC). Factor levels were measured at baseline and several time points post-infusion (30 min, 1h, 2h, 4h, 12h, 24h). A marked decline in circulating coagulation factors was noted after 4 hours, with the greatest reduction observed for Factor II, suggesting preferential inhibitory activity against this factor, likely due to the presence of a neoplastic paraprotein. Therapy with rituximab (anti-CD20 monoclonal antibody) was then introduced at the standard dose of 375 mg/m² weekly for four weeks with complete normalisation of coagulation. Conclusions: This case highlights the diagnostic and therapeutic challenges posed by rare coagulation inhibitors. The successful use of rituximab underscores the relevance of B-cell–directed immunosuppression in managing such complex cases, particularly in the context of clonal B-cell disorders.
2020-09-23 | Paradigm shift for the treatment of hereditary haemophilia: Towards precision medicine.
Patients with haemophilia A (HA) or B (HB) experience spontaneous limb- or life-threatening bleedings which are prevented by regular prophylactic intravenous infusions of the deficient coagulation factor (FVIII or FIX). Prophylaxis with subcutaneous long-acting non-factor products that improve in vivo thrombin generation is now under intensive investigation (concizumab, fitusiran) or successfully employed (emicizumab) in haemophilia patients. Both haemophilia patients with/without inhibitors take advantage of non-factor products employed alone. In those who also need bypassing agents (or FVIII concentrates) for breakthrough bleeds, thromboembolic events and/or thrombotic microangiopathy may occur. By enhancing thrombin generation, prothrombotic mutations co-segregating with FVIII/FIX gene mutations may trigger thrombotic episodes in HA patients carrying acquired thrombogenic factors (e.g. venous catheters). A thorough knowledge of individual needs increasingly contributed to improve comprehensive care and personalize treatments in haemophilia. Integrating genomics, lifestyle and environmental data is expected to be key to: 1) identify which haemophilia patients are less likely to benefit from a given intervention; 2) define optimal dosing and scheduling of bypassing agents (or FVIII) to employ in combination with non-factor products; 3) establish tests to monitor in vivo thrombin generation; 4) improve communication and deliver results to individuals. As individual outcomes will be improved and the risk of adverse events minimized, non-factor products will come into wider use within the haemophilia community, and patients will hopefully have no more risks of breakthrough bleeds. The risks of a normal life for a "former haemophilia patient" is likely to change the treatment landscape and the structure of haemophilia Centers.
2020-05-14 | [Acquired autoimmune haemophilia: Where is the place of rituximab in the treatment strategy? Reflection from a monocentric series of 8 patients and literature review].
Autoimmune acquired haemophilia is a rare autoimmune disease. The purpose of immunosuppressive therapy is to stop the production of autoantibodies that inhibit clotting factors VIII or IX. A corticosteroids-cyclophosphamide combination is recommanded as first-line therapy. From our experience at the University Hospital of Nîmes, we discuss the place of rituximab in the therapeutic arsenal. We report a monocentric observational retrospective study. Our data are discussed in light of literature data, in particular cohorts EACH2 and SACHA. Eight patients (7 with FVIII anibodies) were consecutively included from 2005. The average age was 68.5 years with a male predominance (62.5%). Bleeding manifestations were usually spontaneous and superficial. A pathology, mostly autoimmune or neoplastic, was associated in 5/8 patients. A "by-pass" haemostatic treatment was prescribed for 3/8 patients. Rituximab was prescribed for 5/8 patients, three times as first-line therapy, and always associated with corticosteroids. Three patients received a cyclophosphamid/cortisone combination, two were treated exclusively with oral corticosteroids. Remission was obtained in all patients, without subsequent relapse. The average time to obtain remission under rituximab (after the first injection) was 32.5 days (10-143). The results observed in our series of patients are consistent with the data from the literature. Rituximab appears to be an effective and well-tolerated treatment for autoimmune acquired haemophilia. However, its place remains to be specified.
2011-03-31 | Proteolytic antibodies activate factor IX in patients with acquired hemophilia.
Acquired hemophilia is a rare bleeding disorder characterized by the spontaneous occurrence of inhibitory antibodies against endogenous factor VIII (FVIII). IgG from some patients with acquired hemophilia hydrolyze FVIII. Because of the complex etiology of the disease, no clinical parameter, including the presence of FVIII-hydrolyzing IgG, has been associated with patient's survival or death. Here, we demonstrate the presence of anti-FIX antibodies in acquired hemophilia patients. IgG from some patients were found to hydrolyze FIX. In most cases, IgG-mediated FIX-hydrolysis resulted in FIX activation. IgG-mediated hydrolysis of FIX thus led to the significant generation of activated FIX in 25 of 65 patients. Based on the estimated kinetic parameters, patients' IgG activated up to 0.3nM FIX in 24 hours, an amount that restored thrombin generation in vitro provided the presence of more than or equal to 3% residual FVIII activity in plasma. This work identifies proteolytic IgG as novel molecules able to activate FIX under pathologic conditions. IgG-mediated FIX activation is a prevalent phenomenon among acquired hemophilia patients. The presence of FIX-activating IgG may partly compensate for the antibody-mediated inhibition of endogenous FVIII in restoring thrombin generation. This clinical trial was registered at www.clinicaltrials.gov as #NCT00213473.
1986-04-10 | HTLV III antibodies and immunological alterations in hemophilia patients.
The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.
gene therapies
2026-06-21 | Development of an Agent-Based Model to Investigate Durability of Factor IX Activity in Hemophilia B Patients Treated With Etranacogene Dezaparvovec.
Many currently approved gene therapies use adeno-associated virus (AAV) to deliver DNA sequences encoding protein(s)-of-interest into cells. The AAV viral genome forms stable, circular DNA structures called episomes after entering the nuclei. Therapeutic proteins are then generated in vivo from transcription and translation of these episomes, and long-term durability thus depends on episome stability. Prior modeling work has utilized differential equation-based models to characterize AAV uptake and subsequent protein production. However, episome loss associated with target cell turnover is poorly described with these models. Here, an agent-based model (ABM) to overcome this shortcoming is developed. The liver was used as the example organ as it is known to be self-renewing and has been a common target for gene therapies. In this model, each hepatocyte is an agent, capable of division and death. When transduced, these agents acquire and carry episomes. During cell division, episomes are passed from mother to daughter cells. All episomes are presumed lost when transduced cells die. The ABM was applied to etranacogene dezaparvovec (formerly AMT-061 or CSL222), a liver-targeting gene therapy for hemophilia B consisting of AAV serotype 5 particles encoding a transgene for the Padua variant (R338L) of coagulation factor IX (FIX). ABM-simulated FIX activity in patients receiving this therapy was consistent with clinical observations over more than 2 years following treatment. This ABM was then used to generate 20-year predictions and explore biological mechanisms underlying long-term durability. The ABM framework and approach should be applicable to investigating durability of other AAV-based gene therapies.
2024-09-13 | Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B
Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.
2023-12-15 | HEMOPHILIA: DIAGNOSIS AND INNOVATIVE MANAGEMENT.
Hemophilia is an acquired,X-linked,passive disorder caused by an insufficiency of utilitarian plasma clotting factor VIII (FVIII). In a critical number of cases, the disorder results from a novo mutation. It rarely manifests as an acquired autoimmune process.Research facility thinks about for suspected hemophilia include a total blood cell tally,coagulation ponders, and an FVIII assay. In patients with an established diagnosis of hemophilia, periodic research facility evaluations include screening for the presence of FVIII inhibitors and screening for transfusion-related or transmissible illnesses such as hepatitis and HIV contamination. Estimation of FVIII levels is critical for observing FVIII substitution treatment. Treatment of hemophilia includes prophylaxis, treatment of bleeding episodes, and induction of immune tolerance.Intended for the treatment and rehabilitation of the patients who are taking factor inhibitors and patients have hemophilic synovitis. Treatment for hemophiliacs should ideally be provided by a Hemophilia Day Care center.We discuss innovative management for the prevention of hemophilia through gene therapy,non-replacement therapy,EHL recombinant concentration,etc.we discuss the data from our studies and emerging results from other gene therapy trials in both hemophilia A and B. This analysis will provide evidence and information on the feasibility and data quality/completeness of the hemophilia database to assess the impact of innovative management on hemophilia outcomes in developing countries.We used a statistical method to analyze the data of adult and pediatric patients who come to hemophilia day care center for taking treatment.The data analysis was performed by the data collected monthly at the hemophilia day care center.
2021-01-04 | Gene therapy for hemophilias: the end of phenotypic testing or the start of a new era?
: Hemophilia comprises two distinct genetic disorders caused by missing or defective clotting factor VIII (hemophilia A) or clotting factor IX (hemophilia B). The management of these conditions has been for long based on replacement therapies, but emerging evidence garnered from recent landmark studies suggests that a promising avenue toward routine use of gene therapy is clearly progressing forward, thus generating unavoidable consequences on laboratory hemostasis, especially as pertaining to phenotypic testing. Although it seems likely that widespread use of gene therapy will be associated with a relative decrease of hemostasis tests requests in this patient population due to the relatively stable effect of transgene delivery and persistent production of endogenous clotting factor, some important aspects persuade us that conventional laboratory diagnostics, especially encompassing activated partial thromboplastin time, as well as one-stage and two-stage clotting factor assays, will not be completely voided in the gene therapy era. In particular, phenotypic testing will remain essential for excluding acquired or sporadic cases of hemophilia, for identifying and titrating factor inhibitors, as well as for defining and monitoring the long-term therapeutic effectiveness of gene transfection in hemophiliacs.
2017-12-25 | Baboon envelope pseudotyped lentiviral vectors efficiently transduce human B cells and allow active factor IX B cell secretion in vivo in NOD/SCIDγc-/- mice.
Essentials B cells are attractive targets for gene therapy and particularly interesting for immunotherapy. A baboon envelope pseudotyped lentiviral vector (BaEV-LV) was tested for B-cell transduction. BaEV-LVs transduced mature and plasma human B cells with very high efficacy. BaEV-LVs allowed secretion of functional factor IX from B cells at therapeutic levels in vivo. Background B cells are attractive targets for gene therapy for diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen-presenting cells. Objective Evaluation of human B cells for secretion of clotting factors such as factor IX (FIX) as a possible treatment for hemophilia. Methods We tested here for the first time our newly developed baboon envelope (BaEV) pseudotyped lentiviral vectors (LVs) for human (h) B-cell transduction following their adaptive transfer into an NOD/SCIDγc-/- (NSG) mouse. Results Upon B-cell receptor stimulation, BaEV-LVs transduced up to 80% of hB cells, whereas vesicular stomatitis virus G protein VSV-G-LV only reached 5%. Remarkably, BaEVTR-LVs permitted efficient transduction of 20% of resting naive and 40% of resting memory B cells. Importantly, BaEV-LVs reached up to 100% transduction of human plasmocytes ex vivo. Adoptive transfer of BaEV-LV-transduced mature B cells into NOD/SCID/γc-/- (NSG) [non-obese diabetic (NOD), severe combined immuno-deficiency (SCID)] mice allowed differentiation into plasmablasts and plasma B cells, confirming a sustained high-level gene marking in vivo. As proof of principle, we assessed BaEV-LV for transfer of human factor IX (hFIX) into B cells. BaEV-LVs encoding FIX efficiently transduced hB cells and their transfer into NSG mice demonstrated for the first time secretion of functional hFIX from hB cells at therapeutic levels in vivo. Conclusions The BaEV-LVs might represent a valuable tool for therapeutic protein secretion from autologous B cells in vivo in the treatment of hemophilia and other acquired or inherited diseases.
proteins
2025-12-22 | A Novel Framework for Factor Replacement in Patients Undergoing Liver Transplantation for End Stage Liver Disease
Background The management of coagulopathy and rebalanced hemostasis in end-stage cirrhosis is challenging. Additionally, a certain subset of patients presenting for transplant may have additional acquired or inherited coagulation disorders in addition to liver disease. In patients with these coagulation disorders, there is no updated guidance for isolated factor replacement. Inspired by a case at our institution, we conducted a pilot study to propose a framework to develop a goal-directed dosing strategy for factor repletion in patients presenting for liver transplantation. Methods To determine the level of coagulation factors and the between and within patient variation, factors FVII, FIX, FX, Antithrombin (AT), Protein C (PC), and Protein S (PS) were measured in 41 patients with end stage liver disease and undergoing liver transplantation. Results Coagulation factor data was collected from forty-one patients presenting for liver transplantation. The median level of all measured coagulation factors was below 80% (range 26–76%). The median levels varied widely in studied population (2.1-fold median interquartile range). Notably, measured levels of FIX were strongly correlated with other factors in individual patients: FIX versus FVII (R = 0.81, p < 0.001), FX (R = 0.74, p < 0.001), AT (R = 0.77, p < 0.001), and Protein C (R = 0.86, p < 0.001). Discussion Considering that the median levels were below 80%, for all factors, that levels varied widely among patients, and that levels were highly intercorrelated in an individual patient, it seems appropriate to propose and alternative and empiric target when substituting FIX in patients with hemophilia B before undergoing liver transplantation. We propose the average level of a set of highly inter-correlated coagulation factors as an empiric target when determining goal level for factor repletion.
2025-04-07 | Twenty years of the four-factor prothrombin complex concentrate Octaplex/Balfaxar: A narrative review.
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4F-PCC beyond its approved indications.
2005-03-07 | Activated prothrombin complex concentrate (FEIBA) treatment during surgery in patients with inhibitors to FVIII/IX: the updated Norwegian experience.
Non-activated and activated prothrombin complex concentrates have been used successfully to treat bleeds in haemophilia patients with inhibitors, but most physicians do not consider these products as effective as factor VIII/IX concentrates in non-inhibitor patients. Thus, surgical procedures in inhibitor patients have been performed reluctantly. We have performed 15 minor and six major surgical and invasive diagnostic or therapeutic procedures in eight inhibitor patients with congenital haemophilia A and in two patients with acquired haemophilia. Administration of a loading dose of 100 U kg(-1) of FEIBA followed by 200 U kg (-1) day(-1) in three doses every 8 h for 3 days and then tapering the daily dose to 150-100 U kg(-1), resulted in no severe or unexpected bleeding complications. One adverse event was observed. A 69-year-old man suffered a myocardial infarction the third postoperative day following sigmoidectomy. He was managed safely with opiate analgesia, nitrates and diuretics and the continued use of FEIBA.
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Drug Discovery Landscape
2 orphan drug designations for Acquired hemophilia B, including 2 approved therapies.
2 orphan drug designations for Acquired hemophilia B, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Coagulation factor VIIa (recombinant) [NovoSeven] | proteins | FDA | Approved | Novo Nordisk, Inc. |
Coagulation Factor VIIa (Recombinant) [NovoSeven] | proteins | FDA | Approved | Novo Nordisk, Inc. |
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