Hemophilia therapeutics

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Bispecific Antibody ◽  
Hemophilia A ◽  
Blood Transfusions ◽  
Clotting Factors ◽  
Promising Alternative ◽  
Viii And Ix ◽  
The 1950S ◽  
The Cost

Hemophilia is a genetic hemorrhagic condition marked by uncontrollable and persistent bleeding following surgery or trauma. Hemophilia A is the more common of the two, affecting 1:5000 newborn males in the population. Injecting factor replacement treatments are the most common therapy for hemophilia. The drugs that replaced the clotting factors VIII and IX were developed in the 1950s and 60s. They have been used to treat blood transfusions since the mid-1970s. The development of a humanized bispecific antibody (emicizumab; ACE910) that binds to FIX and FX and replicates the action of FVIII was a key breakthrough in hemophilia therapy. The cost of maintaining this antibody is high, and the feasibility of developing antibodies against the reactant has yet to be determined. Gene therapy is a promising alternative.

scholarly journals Transoperative refusion: a simple and safe method in emergency surgery

2014 ◽  
Vol 41 (4) ◽  
pp. 292-296
Author(s):  
Luiz Carlos Buarque Gusmão ◽  
Sérgio Henrique Chagas Valoes ◽  
José da Silva Leitão Neto
Keyword(s):  
Cost Benefit ◽  
Blood Transfusions ◽  
Factor V ◽  
West Nile Fever ◽  
Clotting Factors ◽  
Blood Contamination ◽  
Simple Method ◽  
Cost Benefit Ratio ◽  
The Cost ◽  
Selection Of

The objective is to reinforce the importance of blood reinfusion as a cheap, safe and simple method, which can be used in small hospitals, especially those in which there is no blood bank. Moreover, even with the use of devices that perform the collection and filtration of blood, more recent studies show that the cost-benefit ratio is much better when autologous transfusion is compared with blood transfusions, even when there is injury to hollow viscera and blood contamination. It is known that the allogeneic blood transfusion carries a number of risks to patients, among them are the coagulation disorders mediated by excess enzymes in the conserved blood, and deficiency in clotting factors, mainly the Factor V, the proacelerin. Another factor would be the risk of contamination with still unknown pathogens or that are not investigated during screening for selection of donors, such as the West Nile Fever and Creutzfeldt-Jacob, better known as "Mad Cow" disease. Comparing both methods, we conclude that blood autotransfusion has numerous advantages over heterologous transfusion, even in large hospitals. We are not against blood transfusions, just do not agree that the patient's own blood is discarded without making sure there will be enough blood in stock to get him out of the hemorrhagic shock.

scholarly journals Novel therapies and current clinical progress in hemophilia A

2017 ◽  
Vol 9 (2) ◽  
pp. 49-61 ◽  
Author(s):  
Pauline Balkaransingh ◽  
Guy Young
Keyword(s):  
Bispecific Antibody ◽  
Hemophilia A ◽  
Venous Access ◽  
Therapeutic Approaches ◽  
Dramatic Decrease ◽  
Mortality And Morbidity ◽  
Novel Treatment ◽  
The Cost ◽  
Turn Over ◽  
Novel Therapeutic

The evolution of hemophilia treatment and care is a fascinating one but has been fraught with many challenges at every turn. Over the last 50 years or so patients with hemophilia and providers have witnessed great advances in the treatment of this disease. With these advances, there has been a dramatic decrease in the mortality and morbidity associated with hemophilia. Even with the remarkable advancements in treatment, however, new and old challenges continue to plague the hemophilia community. The cost of factor replacement and the frequency of infusions, especially in patients with severe hemophilia on prophylaxis, remains a significant challenge for this population. Other challenges include obtaining reliable venous access, especially in younger patients, and the development of neutralizing alloantibodies (inhibitors). The development of extended half-life products, a bispecific antibody which mimics the coagulation function of factor VIII (FVIII) and inhibition of anticoagulation proteins such as antithrombin with antibodies, aptamers or RNA interference technology have offered novel therapeutic approaches to overcome some of these existing challenges. Additionally, ongoing gene therapy research offers a way to possibly cure hemophilia. These novel treatment tools in conjunction with the establishment of an increasing number of comprehensive hemophilia centers and worldwide advocacy efforts have continued to push the progress of hemophilia care to new frontiers. This review highlights and summarizes these novel therapeutic approaches and the current clinical progress of hemophilia A.

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.

Hemophilia Gene Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-48-SCI-48
Author(s):  
Valder R. Arruda
Keyword(s):  
Gene Therapy ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Biological Activities ◽  
Ectopic Expression ◽  
Clotting Factor ◽  
Dependent Manner ◽  
Disease Phenotype ◽  
Clotting Factors ◽  
Hematopoietic Stem

Abstract SCI-48 Over the last decade, five clinical studies on gene therapy for hemophilia A and B using viral and nonviral vectors for liver-restricted or ectopic expression of clotting factor demonstrated safety with no inhibitor formation. Although efficacy in these early phase trials was not achieved because of sustained levels of clotting factor below 1%, these studies form the basis for the second generation of clinical trials. To date, two studies on adeno-associated viral (AAV) vector encoding a FIX transgene for liver-restricted expression are ongoing. In one study using a modified AAV genome pseudotyped with serotype 8, emerging data are encouraging and sustained therapeutic levels of FIX have been obtained in a dose-dependent manner. Novel approaches for hemophilia have been explored targeting hematopoietic stem cells (HSC) using lentiviral vectors for expressing FVIII or FIX genes. Transgene expression under the control of either a non-lineage specific promoter or a platelet-specific promoter showed biological activity and improvement of the disease phenotype. The platelet-restricted approaches did not increase circulating plasma clotting factor levels, but they resulted in enrichment of the factor at the injury site upon platelet activation. An advantage of targeting FVIII expression and storage in platelets is the protection of FVIII from neutralizing antibodies (inhibitors). In this model, platelet-FVIII provided superior hemostasis than elevated plasma FVIII levels upon hemostatic challenges in the microcirculation and macrocirculation. Recently, platelet-restricted expression of human FVIII gene using a lentiviral vector for ex vivo transduction of canine HSC resulted in improvement of the disease phenotype in severe hemophilia A dogs without unwanted immune responses to the transgene. Additional strategies to optimize gene- and/or cell-based approaches have also focused on use of clotting factors with enhanced biological activities will be discussed. Together with the generation of novel vectors, further enhancement of both the efficacy the safety of these approaches is envisioned. Disclosures: Arruda: Pfizer: Research Funding.

Gene therapy approaches for Hemophilia A and B

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Transgene Expression ◽  
Hemophilia A ◽  
Cost Benefit ◽  
Activity Levels ◽  
Protein Therapy ◽  
Human Volunteers ◽  
The Cost

The increasing number of approved gene therapy drugs and the impending licensing of AAV-based gene transfer drugs for Hemophilia A (HA) and hemophilia B (HB) has prompted optimism that equivalent therapeutics for other monogenic bleeding illnesses may be established. Although the benefits of replacement therapies have proven the case for gene therapy of other rare hereditary bleeding disorders, translational gene therapy for these diseases will almost definitely require additional breakthroughs. AAV vector safety in human volunteers was first demonstrated in FIX gene transfer skeletal-muscle-directed investigations. FVII, VWD and GT gene therapy may require comparable breakthroughs to overcome present restrictions. Alloantibodies are present in all hereditary bleeding disorders.A growing body of research indicates AAV gene therapy, especially liver-directed approaches, may be more tolerogenic than protein therapy. Better awareness of variances in transgene expression in male and female participants following AAV liver-directed gene therapy would be critical for autosomal disorders. The mutant transgenes FVIII-BDD and FIX-Padua. respectively considerably assisted gene therapy forHA and HB. The effects of systemically administered SMA in infants were examined. Similarly, the effects of the systemically administered SMA in infants on infants were examined. The effects on hemostatic efficacy due to decreased multimerization. The gene therapy product uniQure NV (Amsterdam, The Netherlands), efficiently replaced FIX-WT with projected improvements in FIX activity levels and without restarting clinical development. With projected high costs of gene therapy, new quality-of-life data is needed to better understand the cost-benefit of such therapies.

Lack of Antibodies to Clotting Factors in the Blood of Hemophiliacs Refractory to Transfusions)

1957 ◽  
Vol 01 (03/04) ◽  
pp. 353-358
Author(s):  
Jorge A Penalver ◽  
R. R Holburn ◽  
R. T Carroll ◽  
L. M Tocantins
Keyword(s):  
Hemophilia A ◽  
Blood Transfusions ◽  
Clotting Time ◽  
Clotting Factors ◽  
Normal Individuals ◽  
Refractory State ◽  
Human Sera ◽  
Fraction I ◽  
Source Of Error ◽  
Positive Results

Summary1. The blood of 11 Hemophilia “A” patients refractory to transfusions has been studied for the presence of precipitins against certain clot-accelerating fractions. The tests were invariably negative. Identical results were observed in 10 Hemophilia “A” patients non-refractory to transfusions, in 2 cases of Hemophilia B, in 5 patients with miscellaneous conditions and in 11 normal individuals.2. When unheated Fraction I of Cohn is used as antigen, false positive results due to formation of fibrin clots were observed with all human sera tested. This may be a source of error in the interpretation of the tests, especially in the blood of refractory Hemophilia “A” patients with an unusually long clotting time and slow prothrombin conversion.3. These observations do not support the hypothesis that the refractory state to blood transfusions observed in some Hemophilia “A” patients is due to the presence of antibodies against certain clot-accelerating fractions of normal plasma.

Recombinant Clotting Factors in the Treatment of Hemophilia

1999 ◽  
Vol 82 (08) ◽  
pp. 516-524 ◽  
Author(s):  
Christine Lee
Keyword(s):  
State Of The Art ◽  
Transmitted Disease ◽  
Rapid Change ◽  
Clotting Factor ◽  
World Federation ◽  
Full Potential ◽  
Clotting Factors ◽  
The World ◽  
Viii And Ix ◽  
The Cost

IntroductionThe field of hemophilia has always been one of rapid change with improvements in clinical practice rapidly following the advances in basic science and clinical research. The major achievements of the last decade have reflected the application of molecular biology, and this has been particularly true for the development of recombinant clotting factors. The interest in developing recombinant factors VIII and IX was driven by the desire for a “safe” clotting factor following the terrible epidemics of transfusion-transmitted disease in the 1970s and 1980s.Although the goals for treatment for hemophilia, as stated by the World Federation of Hemophilia, are “to minimize disability and prolong life, to facilitate general social and physical wellbeing, and to help each patient achieve full potential, while causing no harm,”1 the cost of recombinant clotting factors are comparatively high. As a result, in many instances, the provision has been rationed, even though such therapy is considered state-of-the-art treatment for all patients requiring replacement therapy.

Hemophilia

2016 ◽  
Author(s):  
Aric Parnes ◽  
Lisa Rotenstein
Keyword(s):  
Hemophilia A ◽  
Clinical Manifestations ◽  
Factor Ix ◽  
Hemophilia B ◽  
Bleeding Disorders ◽  
Clotting Factors ◽  
Acute Bleeding ◽  
Clotting Cascade ◽  
Viii And Ix

Hemophilia is a family of rare bleeding disorders characterized by deficiency of clotting factors. Hemophilia A is an inherited deficiency of factor VIII, whereas hemophilia B (Christmas disease) represents a deficiency of factor IX. Both hemophilia A and B are X-linked diseases, with hemophilia A accounting for 80 to 85% of cases and hemophilia B 15 to 20%. Although hemophilia has historically referred to deficiencies of factors VIII and IX, it is important to recognize that similar bleeding disorders can occur with other missing clotting factors, although this is far more rare. This review covers the definition, history, epidemiology, biology/genetics, clinical manifestations, diagnosis, differential diagnosis, treatment, complications, measures of quality of care, and prognosis of hemophilia, as well as future directions. Figures show the clotting cascade, the genetic makeup of severe hemophilia A, an algorithm for diagnosing hemophilia, and hemophilic arthropathy in a patient’s knees. Tables list severity in hemophilia A and B, treatment of acute bleeding in hemophilia A and B, frequency of dosing in acute bleeding, and treatment of acute bleeding with inhibitors. This review contains 4 highly rendered figures, 4 tables, and 59 references.

scholarly journals Hemofilia

Medicinus ◽  
2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael Susanto ◽  
Andree Kurniawan
Keyword(s):  
Autosomal Recessive ◽  
Hemophilia A ◽  
Gene Mutations ◽  
Specific Inhibitor ◽  
Good Prognosis ◽  
Autoimmune Process ◽  
Clotting Factors ◽  
Hemophilic Arthropathy ◽  
Viii And Ix ◽  
Main Complication

Hemophilia A and B are X-linked recessive diseases that are caused by gene mutations in factors VIII adan IX of the blood clotting cycle. Hemophilia C is an autosomal recessive disease caused by a mutation in factor XI, and acquired hemophilia is largely is an autoimmune process. Hemophilia A and B cannot be distinguished clinically, and severe cases can cause bleeding in the joints and lead to chronic hemophilic arthropathy. The main treatment of hemophilia is infusions of factor VIII and IX, and DDAVP in less severe cases. The main complication that can rise from the use of clotting factors is the appearance of specific inhibitor antibodies that can neutralize the work of the factors. Severe cases of hemophilia A and B by itself carries a poor prognosis, but proper treatment throught the use of clotting factors can give a very good prognosis

Hemophilia: An Updated Review

1995 ◽  
Vol 16 (8) ◽  
pp. 290-298
Author(s):  
Beverly Bell ◽  
David Canty ◽  
Michelle Audet
Keyword(s):  
Soft Tissues ◽  
Hemophilia A ◽  
Genetic Disorder ◽  
Von Willebrand Disease ◽  
Clotting Factors ◽  
Genetic Transmission ◽  
Viii And Ix ◽  
Recessive Disorders ◽  
Recessive Defect ◽  
Von Willebrand

Introduction Hemophilia is a genetic disorder that results in either an inactive or inadequate supply of a plasma protein needed for normal blood clotting. The two most common forms are hemophilia A and B, caused by a defect or deficiency in clotting factors VIII and IX, respectively. Both types are X-linked recessive disorders characterized by prolonged bleeding and hemorrhages, typically into joints and soft tissues. Hemophilia C is an autosomal recessive defect that results in a deficiency of factor XI. Marked by bleeding in mucous membranes, hemophilia C exhibits a somewhat different clinical pattern of hemorrhaging than hemophilia A or B but similar to that in von Willebrand disease. This review will focus on hemophilia A and B. Hemophilia has served as a model for the treatment of chronic illness through the comprehensive approach to care. If a child who has hemophilia is managed appropriately with early factor replacement therapy and attempts to avoid the long-term consequences of bleeding, the prospects for a long, full, and healthy life are very good. Epidemiology/Genetic Transmission The incidence of hemophilia A and B is about 15 to 20 per 100 000 males born worldwide and occurs in all races and socioeconomic groups. Hemophilia A, also known as "classical hemophilia," accounts for about 80% of cases of hemophilia, occurs in one of 10 000 male births, and affects about 17 500 individuals in North America.

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