A Novel FVIIa Variant with Increased Potency and Duration of Effect Compared to Wildtype FVIIa. A Study in a Dog Model of Hemophilia A

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2252-2252 ◽  
Author(s):  
Debra Pittman ◽  
Stacey Weston ◽  
Kathleen Shields ◽  
Chuenlei Parng ◽  
Steven Arkin ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Replacement Therapy ◽  
Hemophilia A ◽  
Factor Viia ◽  
Peak Plasma ◽  
Clinical Chemistry ◽  
Clotting Factor ◽  
Duration Of Effect ◽  
Prolonged Duration ◽  
Dose Dependent

Abstract Abstract 2252 Hemophilia patients are treated by replacement therapy, receiving the plasma-derived or recombinant clotting factor in which they are deficient. A significant number of hemophilia patients, however, develop inhibitory antibodies against the factor they receive, becoming refractory to replacement therapy. In these inhibitor patients, hemostasis can be achieved using bypass agents, activated plasma-derived prothombin complex concentrates (aPCC) or recombinant activated Factor VIIa (FVIIa). However, these treatments do not match the efficacy seen in traditional replacement therapy. To overcome this limitation, 813, a modified recombinant human Factor VIIa with enhanced biological properties was developed using a rational protein design approach. 813 was selected from a series of FVIIa variants and is characterized by increased catalytic activity and prolonged duration of effect in vivo. Compared to recombinant wild-type FVIIa, 813 has 7-fold increased catalytic activity, measured by the rate of Factor Xa generation in vitro, both in the presence and absence of tissue factor (TF). 813 was studied in Factor VIII (FVIII)-deficient dogs with NovoSeven RT (wt-FVIIa) as comparator. The FVIII-deficient dogs exhibit a severe hemophilia A phenotype, with less than 1% normal coagulant activity. Dogs were dosed intravenously with 813 or wt-FVIIa and blood and plasma were collected at various time points post dosing. Plasma FVIIa levels were measured using a FVIIa-specific clotting assay. Starting from initial peak plasma levels, a time-dependent decrease in FVIIa plasma concentration was observed for wt-FVIIa and variant. Compared to wt-FVIIa, 813 exhibited a smaller volume of distribution (35–48 mL/kg vs. 108–134 ml/kg), a lower rate of clearance (10–18 mL/hr/kg vs. 45 mL/kg/hr) and consequently an increased dose adjusted exposure. Hemophilia A dogs have a prolonged activated partial thromboplastin time (aPTT); treatment with wt-FVIIa or 813 led to a dose-dependent decrease in aPTT. At equivalent doses the peak effect of 813 on decreasing aPTT was approximately two-fold compared to wt-FVIIa. Similar dose-dependent effects were observed when studying whole blood clotting profiles by thromboelastography (TEG). Treatment effects were seen for all TEG parameters monitored (time to clotting onset, rate and strength of clot formation). However, compared to wt-FVIIa, 813 given at equivalent doses caused significantly stronger effects on all TEG parameters; acute peak effects on TEG parameters measured for 813 at 10 ug/kg, were similar to those seen with 50 ug/kg wt-FVIIa. This difference became even more pronounced when monitoring treatment effect over time. All dogs used in this study were monitored throughout the study for possible treatment-related changes; both 813 and wt-FVIIa were well tolerated. No overt adverse events, no significant changes in plasma clinical chemistry or cellular blood counts were observed. In conclusion, 813 is a novel FVIIa protein with increased potency, prolonged duration of effect and a preclinical safety profile comparable to wt-FVIIa. 813 is currently in early clinical development for acute and prophylactic treatment of hemophilia patients with inhibitors. Disclosures: Pittman: Pfizer: Employment. Weston:Pfizer: Employment. Shields:Pfizer: Employment. Parng:Pfizer: Employment. Arkin:Pfizer: Employment. Madison:Catalyst Biosciences: Employment. Nichols:Pfizer: Research Funding. Fruebis:Pfizer: Employment.

scholarly journals In Hemophilia Α Plasma Treated with Emicizumab, Factor IX Activation By Factor VIIa Drives Thrombin Generation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Dougald Monroe ◽  
Mirella Ezban ◽  
Maureane Hoffman
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Factor Ix ◽  
Factor X ◽  
Dose Dependent

Background.Recently a novel bifunctional antibody (emicizumab) that binds both factor IXa (FIXa) and factor X (FX) has been used to treat hemophilia A. Emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A; however there are patients that still experience bleeding. An approach to safely and effectively treating this bleeding in hemophilia A patients with inhibitors is recombinant factor VIIa (rFVIIa). When given at therapeutic levels, rFVIIa can enhance tissue factor (TF) dependent activation of FX as well as activating FX independently of TF. At therapeutic levels rFVIIa can also activate FIX. The goal of this study was to assess the role of the FIXa activated by rFVIIa when emicizumab is added to hemophilia A plasma. Methods. Thrombin generation assays were done in plasma using 100 µM lipid and 420 µM Z-Gly-Gly-Arg-AMC with or without emicizumab at 55 µg/mL which is the clinical steady state level. The reactions were initiated with low (1 pM) tissue factor (TF). rFVIIa was added at concentrations of 25-100 nM with 25 nM corresponding to the plasma levels achieved by a single clinical dose of 90 µg/mL. To study to the role of factor IX in the absence of factor VIII, it was necessary to create a double deficient plasma (factors VIII and IX deficient). This was done by taking antigen negative hemophilia B plasma and adding a neutralizing antibody to factor VIII (Haematologic Technologies, Essex Junction, VT, USA). Now varying concentrations of factor IX could be reconstituted into the plasma to give hemophilia A plasma. Results. As expected, in the double deficient plasma with low TF there was essentially no thrombin generation. Also as expected from previous studies, addition of rFVIIa to double deficient plasma gave a dose dependent increase in thrombin generation through activation of FX. Interestingly addition of plasma levels of FIX to the rFVIIa did not increase thrombin generation. Starting from double deficient plasma, as expected emicizumab did not increase thrombin generation since no factor IX was present. Also, in double deficient plasma with rFVIIa, emicizumab did not increase thrombin generation. But in double deficient plasma with FIX and rFVIIa, emicizumab significantly increased thrombin generation. The levels of thrombin generation increased in a dose dependent fashion with higher concentrations of rFVIIa giving higher levels of thrombin generation. Conclusion. Since addition of FIX to the double deficient plasma with rFVIIa did not increase thrombin generation, it suggests that rFVIIa activation of FX is the only source of the FXa needed for thrombin generation. So in the absence of factor VIII (or emicizumab) FIX activation does not contribute to thrombin generation. However, in the presence of emicizumab, while rFVIIa can still activate FX, FIXa formed by rFVIIa can complex with emicizumab to provide an additional source of FX activation. Thus rFVIIa activation of FIX explains the synergistic effect in thrombin generation observed when combining rFVIIa with emicizumab. The generation of FIXa at a site of injury is consistent with the safety profile observed in clinical use. Disclosures Monroe: Novo Nordisk:Research Funding.Ezban:Novo Nordisk:Current Employment.Hoffman:Novo Nordisk:Research Funding.

Long Term Dose-Dependent Correction of Hemophilia A Dogs Using AAV-8 and AAV-9-Mediated FVIII Gene Transfer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 999-999
Author(s):  
Denise E. Sabatino ◽  
Amy M. Lange ◽  
Melinda Mucci ◽  
Rita Sarkar ◽  
Aaron M. Dillow ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Dose Group ◽  
Low Dose ◽  
Hemophilia A ◽  
Clotting Factor ◽  
High Dose ◽  
Functional Assay ◽  
Dependent Manner ◽  
Aav Vector ◽  
Dose Dependent

Abstract Hemophilia A (HA) is an X-linked bleeding disorder characterized by deficiency in clotting factor VIII (FVIII). Current treatment for hemophilia is protein replacement therapy while a gene-based therapy would provide continuous expression of even low levels of FVIII protein (>1% of normal) that is likely to improve the disease phenotype. It is challenging to utilize an AAV-mediated gene transfer approach for the FVIII cDNA (4.4kb) since the AAV vector can only efficiently accommodate a <5.3kb transgene cassette. The FVIII protein is composed of 2 chains -the heavy chain (HC) and the light chain (LC). FVIII undergoes proteolytic cleavage and processing of the 2 individual chains that form the active FVIII protein. In other studies in HA dogs (n=8), no dose-response and AAV serotype-dependent FVIII expression has been documented, which illustrates the difficulties in using a FVIII single-chain approach. We have utilized a 2-chain approach in which the 2.4kb LC cDNA is packaged in one AAV vector while the 2.5kb HC is packaged into a second AAV vector. Each construct contains a 695bp thyroxine-binding globulin gene promoter/enhancer fused to a 175bp intron along with a 263bp SV40 poly A signal. For this approach the LC and HC vectors packaged into either AAV8 or AAV9 were administered to HA dogs via the hepatic artery. Two male HA dogs received HC and LC in AAV8 and 2 male dogs received HC and LC in AAV9 at doses of 6x1012gc/vector/kg (low dose) or 1.25x1013gc/v/kg (high dose). At 150 days after vector infusion, the high dose group expressed FVIII at levels of 4.8% (AAV8) and 3% (AAV9) as detected by a functional assay (Coatest assay). FVIII remained stable for 797 days (AAV8) and >200 days (AAV9) (the longest time points to date) without any evidence of antibody formation to the transgene. In the low dose group at 150 days, FVIII levels were 1.5% (AAV8) and 0.5% (AAV9) cFVIII activity and were maintained in a follow up period of >150 days (AAV8) and >700 days (AAV9) without formation of antibodies to FVIII. Thus, no major differences between AAV8 and AAV9 vectors were observed. The transgene product is also functional based on shortening of whole blood clotting time (baseline values >50 min), in a dose-dependent manner, 10–15 min and 16–20 min for the high and low dose cohorts, respectively. Interestingly, high dose injection of AAV8 to 2 female HA dogs (1.25x1013 and 3x1013gc/v/kg) results in FVIII levels of 1–2%, which is consistent with data obtained in mice on the poor performance of AAV in mediating gene transfer to liver in female animals. Liver function tests and other blood chemistries were transiently elevated after the surgical procedure and were in normal limits within 4 days. Importantly, all dogs did not develop antibodies to FVIII. These findings suggest that FVIII chains efficiently assemble in vivo without increasing the protein immunogenicity. The 4 male dogs have remained asymptomatic with no spontaneous bleeds, whereas >20 bleeding episodes were expected for this group since untreated dogs require 5.5 plasma infusions/year. These data demonstrate for the first time, dose-dependent sustained expression of functional cFVIII in HA dogs by AAV8 and AAV9 vectors without formation of antibodies to cFVIII.

Safety and Efficacy of an Adeno Associated Virus-Based Vector Carrying the Human Clotting Factor IX Gene (AAV5-hFIX) As Studied in Non-Human Primates

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4800-4800 ◽  
Author(s):  
Bart Nijmeijer ◽  
Harald Petry ◽  
Lisa Spronck ◽  
Corina Van Der Kruijssen ◽  
Jorgen Petersen ◽  
...  
Keyword(s):  
Transgene Expression ◽  
Dose Group ◽  
Clinical Chemistry ◽  
Factor Ix ◽  
Clotting Factor ◽  
Adeno Associated Virus ◽  
Expression Levels ◽  
Normal Human ◽  
Dose Dependent ◽  
Vector Dna

Abstract Restoration of clotting Factor IX (FIX) expression through gene transfer is a promising option for the treatment of Hemophilia B. We have developed an Adeno-Associated Virus serotype 5-based vector containing the human coagulation factor IX gene (AAV5-hFIX), in our fully scalable GMP-compliant baculovirus-based production platform. To evaluate safety and efficacy of AAV5-hFIX in a relevant preclinical model, 4 groups of 3 cynomolgus macaques were dosed intravenously with 5x1011, 5x1012, 2.5x1013 and 0.93x1014 vector genome copies (gc) per kg body weight, respectively. Blood was sampled periodically, from 4 weeks pre-trial until necropsy at 26 weeks after dosing. Clinical chemistry and inflammation markers were assessed using standard techniques. Circulating human FIX protein levels were assessed by hFIX-specific ELISA. At necropsy, full histopathological examination was performed, and selected tissues were assessed for the presence of vector DNA and -RNA by quantitative PCR and RT-PCR, respectively. No signs of adverse reactions were observed in any of the animals throughout the in-life period. Clinical chemistry and inflammatory markers were unaffected by treatment with AAV5-hFIX. At necropsy, there were no macroscopic or microscopic tissue findings that could be attributed to the vector. Infusion of AAV5-hFIX resulted in dose-dependent circulating levels of hFIX protein. In the highest-dose group, hFIX levels peaked to 30% of normal human levels seven days after administration, and stabilized around 10-15% of normal human levels over the remaining observation period of 6 months. In the lowest-dose group, hFIX levels did not increase above 1%. Analysis of tissues after necropsy revealed dose-dependent vector DNA delivery to the liver, and concurrent dose-dependent transgene expression levels. No significant off-target expression was observed. In one animal, circulating hFIX levels decreased to baseline one month after vector administration. This decrease was shown to be caused by the development of xenoreactive hFIX-specific antibodies. This immune response was limited to sequestration of hFIX from the circulation, and did not entail T cell reactivity towards transduced hepatocytes as the transgene expression levels in the liver of this animal were comparable to those observed in its group mates. Based on the observed expression levels, and by extrapolating the dose one-on-one between non-human primates and humans, the Minimum Anticipated Biological Effect Level (MABEL) in man is 5x1012 gc/kg. In conclusion, administration of AAV5-hFIX to non-human primates was well tolerated without any noticeable adverse effects, and resulted in (i) dose-dependent transgene delivery to the liver, (ii) liver-specific transgene expression, and (iii) circulating human FIX protein to levels that are expected to be of significant clinical benefit in the setting of hemophilia B. Disclosures Nijmeijer: uniQure BV: Employment. Petry:uniQure B. V,: Employment. Spronck:uniQure BV: Employment. Van Der Kruijssen:uniQure BV: Employment. Petersen:uniQure: Consultancy. Salmon:uniQure B. V.: Employment.

scholarly journals Alternative Strategies for Gene Therapy of Hemophilia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 197-202 ◽  
Author(s):  
Robert R. Montgomery ◽  
Qizhen Shi
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Replacement Therapy ◽  
Hemophilia A ◽  
Ectopic Expression ◽  
Factor Vii ◽  
Clotting Factor ◽  
Large Animal ◽  
Clotting Factors ◽  
Hematopoietic Stem

Abstract Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for “curing” hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.

scholarly journals The risk of venipuncture in newborn with severe hemophilia: Case report of a large elbow hemorrhage and literature review of compartment syndrome

2021 ◽  
Vol 13 (2) ◽  
Author(s):  
Giuseppe Lassandro ◽  
Anna Amoruso ◽  
Valentina Palladino ◽  
Viviana Valeria Palmieri ◽  
Paola Giordano
Keyword(s):  
Literature Review ◽  
Replacement Therapy ◽  
Compartment Syndrome ◽  
Hemophilia A ◽  
Massive Bleeding ◽  
Clotting Factor ◽  
Invasive Technique ◽  
Safe Procedure ◽  
Local Pressure ◽  
Rapid Replacement

Hemophilias are hemorrhagic congenital rare diseases. The gold standard of therapy in hemophilics is the intravenously replacement therapy. We can infuse intravenously plasma derived factors (FVIII for Hemophilia A and FIX for Hemophilia B) or recombinant products (i.e. clotting factor synthetically produced). Venipuncture is not a safe procedure in subjects with hemorrhagic diseases. It is considered an invasive technique with potential massive bleeding and it requires standardized procedures to prevent complications. Local pressure after the procedure (with eventually ice rest) must be always done. In case of bleeding a rapid replacement therapy must be conducted. A severe complication in hemophilia is compartment syndrome. We report a case of massive bleeding in a hemophilic newborn after venipuncture and a literature review of compartment syndrome in hemophiliacs. The aim of this paper is to help physicians in the clinical management to prevent the evolution of a massive bleeding in compartment syndrome.

Current Concepts of Hemostasis

2004 ◽  
Vol 100 (3) ◽  
pp. 722-730 ◽  
Author(s):  
Harold R. Roberts ◽  
Dougald M. Monroe ◽  
Miguel A. Escobar ◽  
Richard B. Weiskopf
Keyword(s):  
Replacement Therapy ◽  
Conventional Therapy ◽  
Perioperative Management ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Clotting Factor ◽  
Excessive Bleeding ◽  
Off Label ◽  
Clotting Factor Concentrates

The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.

Suppression of Inhibitor Formation in Protein and Gene Therapy for Hemophilia Using Ex Vivo Expanded Treg

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 13-13
Author(s):  
Debalina Sarkar ◽  
David M Markusic ◽  
Cox Terhorst ◽  
Todd Brusko ◽  
Roland W Herzog
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Ex Vivo ◽  
Coagulation Factors ◽  
Hemophilia B ◽  
Clotting Factor ◽  
Treg Population

Abstract Abstract 13 Hemophilia A and B result from deficiency in clotting factor VIII (FVIII) or IX (FIX), respectively. In a subset of patients, treatment by factor replacement therapy is limited by formation of inhibitory antibodies to the clotting factors, representing a serious complication that increases risks of morbidity and mortality. Immune responses to the therapeutic coagulation factors are also a concern in newly emerging gene therapies. Regulatory T cells (Treg) offer to be a novel alternative pathway toward immune tolerance. Treg has been identified as a major component of immune tolerance to coagulation factors in pre-clinical studies. Therefore, we hypothesize that ex vivo expanded autologous Treg can suppress inhibitor formation. Our study seeks to test this approach in hemophilic mice. Initially, we optimized in vitro expansion of murine BALB/c-derived Treg. Using flow sorting, GFP+ cells were purified (>98% purity) from spleens of BALB/c knock-in mice containing a GFP reporter linked to FoxP3 expression with an IRES sequence. Sorted cells were stimulated in culture using anti-CD28/anti-CD3 beads in the presence of high-level IL-2 (1000 U/ml). IL-2 was replenished every second day in culture. After ∼1 week, cells were freshly stimulated. At the end of 2 weeks, viability, purity, and FoxP3/GFP expression was confirmed. Greater than 30-fold expansion was repeatedly accomplished. Assumming a dose of 1×106 Treg/mouse, expansion is sufficiently robust to treat >30 mice starting with Treg from 2–3 donor mice. Ex vivo expanded Tregs were adoptively transferred to male hemophilia A mice (BALB/c F8e16 −/−), which were then treated with F.VIII (1 IU human B domain-deleted F.VIII, IV, once per week) for two months. Bethesda assays demonstrated that Treg transplant had effectively suppressed inhibitor formation. Inhibitor titers in control mice were 15–20 BU at 1 month and 30–40 BU at two months. In contrast, Treg treated mice (n=5 per group) formed at most low-titer inhibitors (2–3 BU for both time points). By 2 months, peripheral Treg frequencies had returned to near baseline. To further demonstrate presence of a Treg population capable of suppressing antibody formation against F.VIII, a secondary transfer of sorted CD4+CD25+ splenocytes was performed. Recipient hemophilia A mice were immunized against F.VIII in adjuvant. Compared to mice receiving control Treg, there was significant (P<0.05) suppression of inhibitor formation against F.VIII. In other experiments, Treg therapy was also able to significantly reduce inhibitor titers in hemophilia A mice with pre-existing F.VIII inhibitors. We chose hemophilia A mice (n=6) that developed on average 25 BU from F.VIII replacement therapy. Half of these received Treg transplant, and all mice received 8 more weeks of F.VIII treatment. Inhibitor titers in the control group increased to ∼100 BU. Treg therapy substantially reduced this response (to 15–20 BU, P<0.001). In order to evaluate Treg therapy for hemophilia B, BALB/c F9 −/− × FoxP3-GFP mice were generated. Treg were isolated from these mice as described above, expanded in vitro, and transferred to (BALB/c F9 −/−) hemophilia B mice. Two days later, to test their effectiveness in a gene therapy setting, these mice were treated by intramuscular injection of AAV1 vector expressing human F.IX. By 6 weeks after gene transfer, control mice had formed high-titer antibody against hF.IX (>20 mg IgG/ml plasma, ∼ 10 BU). In contrast, anti-hF.IX formation was undetectable in mice that had received Treg prior to vector administration (n=4/group). While perhaps not as potent as antigen-specific Treg, our data demonstrate the ability of highly purified and ex vivo expanded bulk Treg to control inhibitor formation and thus support their utility for tolerance induction in hemophilia. Their effectiveness may involve emergence of a more specific Treg population after repeated in vivo exposure to antigen. In gene therapy, Treg transplant may be a more desirable alternative to use of immune suppressive drugs. Providing additional immune regulation around the time of vector administration, i.e. when activation signals are provided to the immune system, could be sufficient to prevent immune rejection long-term while inducing antigen-experienced Treg for durable tolerance. Disclosures: Herzog: Genzyme Corp.: Royalties, AAV-FIX technology, Royalties, AAV-FIX technology Patents & Royalties.

scholarly journals Toward optimal therapy for inhibitors in hemophilia

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 364-371 ◽  
Author(s):  
Christine L. Kempton ◽  
Shannon L. Meeks
Keyword(s):  
Hemophilia A ◽  
Factor Viia ◽  
High Titer ◽  
Tolerance Induction ◽  
Clotting Factor ◽  
Significant Burden ◽  
Prophylactic Use ◽  
Bypassing Agents ◽  
Activated Prothrombin Complex Concentrates ◽  
The Individual

Abstract Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ∼50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ∼60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

scholarly journals Factor VIII products: key aspects of development, clinical research and use (part 1)

2021 ◽  
Vol 21 (1) ◽  
pp. 39-49
Author(s):  
Zh. I. Avdeeva ◽  
A. A. Soldatov ◽  
V. P. Bondarev ◽  
V. D. Mosyagin ◽  
V. A. Merkulov
Keyword(s):  
Factor Viii ◽  
Replacement Therapy ◽  
Blood Clotting ◽  
Hemophilia A ◽  
Clinical Manifestations ◽  
Current Data ◽  
Clotting Factor ◽  
World Federation ◽  
The World ◽  
Blood Clotting Factor

According to the World Federation of Hemophilia (WFH), there are currently about 400 thousand patients with hemophilia in the world. Severe clinical manifestations of the disease associated with a genetically determined deficiency of blood clotting factor activity require continuous replacement therapy with blood clotting medicines. Long-term use of protein-based medicines often leads to the formation of specific antibodies, which causes a decrease in or loss of efficacy of the medicine or results in severe adverse reactions, including anaphylaxis. Therefore, it is important to search for new optimal approaches to hemophilia treatment, which requires the development of new blood clotting factor products, improvement of the production technology for already authorised products, as well as the use of non-factor products. The aim of the study was to present the results of the analysis of key issues related to the development and characteristics of plasma-derived and recombinant factor VIII products, new approaches to hemophilia A treatment, including the use of non-factor products. The review summarises current data on the etiology, clinical manifestations, and complications of hemophilia A treatment. It provides information on the blood clotting factor products (plasma-derived and recombinant) used as replacement therapy. It also provides information on advanced research projects for the development of new biotechnology-derived products which have good prospects of successful clinical use.

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