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Hematology. American Society of... Dec 2022The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular... (Review)
Review
The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular diagnostic for hemophilia, followed by the development of recombinant clotting factor replacement therapy. Now gene therapy beckons on the back of decades of research that has brought us to the final stages of the approval of 2 products in Europe and United States, thus heralding a new era in the treatment of the hemophilias. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. There are several other gene therapy approaches in earlier stages of development. These approaches entail a one-off infusion of a genetically modified adeno-associated virus (AAV) engineered to deliver either the FVIII or FIX gene to the liver, leading to the continuous endogenous synthesis and secretion of the missing coagulation factor into the circulation by the hepatocytes, thus preventing or reducing bleeding episodes. Ongoing observations show sustained clinical benefit of gene therapy for >5 years following a single administration of an AAV vector without long-lasting or late toxicities. An asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer that has the potential to eliminate the transduced hepatocytes in the absence of treatment with immunosuppressive agents such as corticosteroids. The current state of this exciting and rapidly evolving field, as well as the challenges that need to be overcome for the widespread adaptation of this new treatment paradigm, is the subject of this review.
Topics: Humans; Genetic Vectors; Hemophilia A; Hemophilia B; Genetic Therapy; Factor VIII; Factor IX; Dependovirus; Blood Coagulation Factors
PubMed: 36485127
DOI: 10.1182/hematology.2022000388 -
Journal of Thrombosis and Thrombolysis Aug 2021Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common... (Review)
Review
Blood coagulation factor X/Xa sits at a pivotal point in the coagulation cascade and has a role in each of the three major pathways (intrinsic, extrinsic and the common pathway). Due to this central position, it is an attractive therapeutic target to either enhance or dampen thrombin generation. In this brief review, I will summarize key developments in the molecular understanding of this critical clotting factor and discuss the molecular basis of FX deficiency, highlight difficulties in expressing recombinant factor X, and detail two factor X variants evaluated clinically.
Topics: Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Factor X; Factor Xa; Humans; Molecular Biology; Thrombin
PubMed: 33886037
DOI: 10.1007/s11239-021-02456-w -
Physiological Reviews Jan 2013Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a... (Review)
Review
Hemostasis encompasses the tightly regulated processes of blood clotting, platelet activation, and vascular repair. After wounding, the hemostatic system engages a plethora of vascular and extravascular receptors that act in concert with blood components to seal off the damage inflicted to the vasculature and the surrounding tissue. The first important component that contributes to hemostasis is the coagulation system, while the second important component starts with platelet activation, which not only contributes to the hemostatic plug, but also accelerates the coagulation system. Eventually, coagulation and platelet activation are switched off by blood-borne inhibitors and proteolytic feedback loops. This review summarizes new concepts of activation of proteases that regulate coagulation and anticoagulation, to give rise to transient thrombin generation and fibrin clot formation. It further speculates on the (patho)physiological roles of intra- and extravascular receptors that operate in response to these proteases. Furthermore, this review provides a new framework for understanding how signaling and adhesive interactions between endothelial cells, leukocytes, and platelets can regulate thrombus formation and modulate the coagulation process. Now that the key molecular players of coagulation and platelet activation have become clear, and their complex interactions with the vessel wall have been mapped out, we can also better speculate on the causes of thrombosis-related angiopathies.
Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Blood Platelets; Cell Communication; Feedback, Physiological; Hemostasis; Humans; Platelet Activation; Signal Transduction
PubMed: 23303912
DOI: 10.1152/physrev.00016.2011 -
Haemophilia : the Official Journal of... May 2022Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal...
INTRODUCTION
Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal prophylaxis in managing patients with haemophilia A with inhibitors. We describe the emicizumab rollout and pharmacokinetic strategies and their use in paediatric patients.
METHODS
The evolving real-world experience in using emicizumab has confirmed its safety, efficacy and pharmacokinetic profile in paediatric, adolescent and adult patients receiving emicizumab at various prophylactic dosing regimens. The emicizumab current global rollout includes over 100 countries with 29 low to middle-income countries accessing emicizumab through the World Federation of Haemophilia (WFH) Humanitarian Aid Program. The diversity of emicizumab dosing and pharmacokinetic tools such as the Calibra® and the WAPPS-Hemo platforms make it possible to achieve prophylaxis goals in line with the WFH Haemophilia treatment guidelines recommendations, with minimal drug wastage. The emerging experience from long term clinical trials and long-term real-world follow-up confirm the safety, efficacy, and pharmacokinetic profile of emicizumab in paediatric haemophilia A patients. A few questions, including inhibitor recurrence, concurrent use of emicizumab with various replacement therapies and inhibitor eradication, are being addressed through multiple ongoing clinical studies.
CONCLUSION
The current global rollout of emicizumab is remarkable, and versatile dosing regimens and evolving pharmacokinetic tools such as the Calibra® and WAPPS-Hemo platforms make it a treatment choice available also for pharmacokinetic guided personalised treatment. Data from paediatric studies are consistent with those seen in adolescent and adult Haemophilia A.
Topics: Adolescent; Adult; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation Factors; Child; Factor VIII; Hemophilia A; Humans
PubMed: 35521723
DOI: 10.1111/hae.14524 -
Deutsches Arzteblatt International Nov 2019Approximately 4550 persons were under treatment for hemophilia in Germany in 2017. The condition is currently treated with intravenous supplementa- tion of the missing... (Review)
Review
BACKGROUND
Approximately 4550 persons were under treatment for hemophilia in Germany in 2017. The condition is currently treated with intravenous supplementa- tion of the missing clotting factor, either prophylactically or as needed. Newer treat- ment options rely on novel mechanisms of action.
METHODS
This review is based on pertinent publications retrieved by a selective search in MEDLINE/PubMed, as well as on expert opinions and the recommenda- tions of specialty societies.
RESULTS
Randomized controlled trials have shown that, in children aged 30 months to 6 years, prophylactic clotting-factor supplementation yields a markedly lower an- nual rate of hemorrhage than supplementation as needed: 3.27 (standard deviation [SD] 6.24) for the former vs. 17.69 (SD 9.25) for the latter. A similar large effect was seen in patients aged 12 to 50 years, with hemorrhage rates of 1.9 (SD 4.1) vs. 28.7 (SD 18.8). Clotting-factor preparations with longer half-lives make it possible to lessen the frequency of administration and to prevent subtherapeutic factor levels. A number of alternatives to clotting-factor supplementation have recently been approved or are currently being clinically tested. These new drugs are injected sub- cutaneously and have a longer half-life, possibly enabling better protection against bleeding than the current standard treatment. A further advantage of some of these drugs is that they can be given even in the presence of inhibitors to factor VIII. In addition, initial (phase I) clinical trials of gene therapy have been performed suc- cessfully for both hemophilia A and hemophilia B.
CONCLUSION
Now that new alternatives to classic supplementation therapy are be- coming available, pertinent treatment algorithms for patients with hemophilia will have to be developed. It is still unclear to what extent the new drugs might supplant clotting factor supplementation as the first line of treatment.
Topics: Blood Coagulation Factors; Clinical Trials, Phase I as Topic; Germany; Hemophilia A; Hemophilia B; Hemorrhage; Humans; Randomized Controlled Trials as Topic
PubMed: 31847949
DOI: 10.3238/arztebl.2019.0791 -
Clinical Pharmacokinetics Jan 2021Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL) and some... (Review)
Review
Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL) and some patients with moderate hemophilia (0.01-0.05 IU mL) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.
Topics: Blood Coagulation Factors; Child; Deamino Arginine Vasopressin; Hemophilia A; Humans
PubMed: 32936401
DOI: 10.1007/s40262-020-00936-5 -
Deutsches Arzteblatt International Dec 2022AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does... (Review)
Review
BACKGROUND
AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does not suffer from the limitations of the current standard treatment (regular prophylactic intravenous injections of the missing clotting factor; subcutaneous injection of a bispecific antibody in hemophilia A) and can, it is hoped, raise the concentration of the missing clotting factor over the long term. AAV-based gene therapy can only be performed once, however, because of the generation of antibodies to AAV.
METHODS
This review is based on publications retrieved by a selective search in the MEDLINE/PubMed database employing the relevant key words, supplemented by expert opinions and the recommendations of the relevant medical societies.
RESULTS
Data from non-randomized phase 1 to phase 3 trials reveal an adequate expression of factors VIII and IX in patients with mostly severe hemophilia A or B. Even though they were no longer receiving prophylactic treatment, most patients experienced a considerable reduction, by 53% to 96%, in the number of bleedings compared to previous therapy. Persistently elevated factor levels have been described for up to six years in hemophilia A and up to eight years in hemophilia B. The most common side effect of gene therapy is an inflammatory response with elevated alanine aminotransferase levels (17% to 89%, depending on the study), which may be associated with a reduced clotting factor level and requires treatment with transient immunosuppression.
CONCLUSION
Gene therapy for hemophilia holds out the prospect of freedom from hemorrhage without the need for regular treatment with drugs. The various steps that need to be carried out in gene therapy should be coordinated in a graded and partly overlapping integrated care model (a so-called hub-and-spoke model). Electronic platforms should be used for data acquisition and transmission.
Topics: Humans; Hemophilia A; Hemophilia B; Blood Coagulation Factors; Hemorrhage; Genetic Therapy
PubMed: 36468250
DOI: 10.3238/arztebl.m2022.0353 -
Journal of Thrombosis and Haemostasis :... Jun 2015Hemophilia, when severe, leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions. Most patients must limit their... (Review)
Review
Hemophilia, when severe, leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions. Most patients must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In 2014, new therapeutic factor VIII and IX products were approved in Canada and the U.S. Over the next couple of years, other new factor products will likely be approved. These new factors have been engineered to have improved pharmacokinetic properties, including extended half-life in circulation, thus providing major therapeutic advances for patients with hemophilia. In the completed clinical trials, over 700 patients have successfully used these longer acting products regularly for more than one year. These promising new therapies should allow patients with hemophilia to use fewer infusions to prevent spontaneous bleeding or to treat bleeding episodes, and to provide appropriate clotting factor levels for different physical activities.
Topics: Animals; Blood Coagulation Factors; Drug Discovery; Drugs, Investigational; Hemophilia A; Hemorrhage; Hemostasis; Hemostatics; Humans; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 26149018
DOI: 10.1111/jth.12912 -
Journal of Thrombosis and Haemostasis :... Aug 2016Factor XII is a mysterious plasma protein without a clear physiologic function. It was identified as a clotting factor, but has no clear role in hemostasis. However,... (Review)
Review
Factor XII is a mysterious plasma protein without a clear physiologic function. It was identified as a clotting factor, but has no clear role in hemostasis. However, FXII also contributes to the production of bradykinin, a short-lived inflammatory peptide. A growing body of mechanistic research from animal models indicates that FXII contributes to thrombotic disease by triggering excessive coagulation. FXII is evolutionarily conserved, suggesting that this molecule does have a physiologic function. This leads to intriguing questions: What does FXII really do? Is it even a real clotting factor at all? Before the groundbreaking discovery of a role for FXII in thrombotic disease, many studies investigated the biochemical properties of FXII and its activators. In this review, we highlight several biochemical studies that reveal much about the natural behavior of FXII. On the basis of these findings, it is possible to draft a conceptual model to explain how FXII reacts to surface materials. We then discuss how this model applies to the activities of FXII in its natural environment. There are two tentative physiologic functions of FXII that can operate exclusively: (i) maintenance of thrombus stability; (ii) local regulation of vascular permeability. Either, or both, of these natural functions may explain the evolutionary development and maintenance of FXII.
Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Bradykinin; Coagulants; Factor XII; Hemostasis; Humans; Inflammation; Permeability; Prekallikrein; Thrombosis
PubMed: 27282310
DOI: 10.1111/jth.13383 -
Transfusion May 2014Pathogen safety is crucial for plasma-derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products,... (Review)
Review
Pathogen safety is crucial for plasma-derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products, is collected by plasmapheresis (source plasma) or derived from whole blood donations (recovered plasma). The primary measures regarding pathogen safety are selection of healthy donors donating in centers with appropriate epidemiologic data for the main blood-transmissible viruses, screening donations for the absence of relevant infectious blood-borne viruses, and release of plasma pools for further processing only if they are nonreactive for serologic markers and nucleic acids for these viruses. Despite this testing, pathogen inactivation and/or removal during the manufacturing process of plasma-derived clotting factor concentrates is required to ensure prevention of transmission of infectious agents. Historically, hepatitis viruses and human immunodeficiency virus have posed the greatest threat to patients receiving plasma-derived therapy for treatment of hemophilia or von Willebrand disease. Over the past 30 years, dedicated virus inactivation and removal steps have been integrated into factor concentrate production processes, essentially eliminating transmission of these viruses. Manufacturing steps used in the purification of factor concentrates have also proved to be successful in reducing potential prion infectivity. In this review, current techniques for inactivation and removal of pathogens from factor concentrates are discussed. Ideally, production processes should involve a combination of complementary steps for pathogen inactivation and/or removal to ensure product safety. Finally, potential batch-to-batch contamination is avoided by stringent cleaning and sanitization methods as part of the manufacturing process.
Topics: Blood Coagulation Factors; Blood Safety; Blood-Borne Pathogens; Filtration; Freeze Drying; Hot Temperature; Humans; Pasteurization; Plasma; Risk Assessment; Risk Reduction Behavior
PubMed: 24117799
DOI: 10.1111/trf.12423