Development of neutralizing antibodies in application of various concentrates of blood coagulation factor VIII in the treatment of hemophilia A

2021 ◽  
Author(s):  
Н.И. Зозуля
Keyword(s):  
Factor Viii ◽  
Cell Line ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Chinese Hamster ◽  
Coagulation Factor ◽  
Human Cell Line ◽  
Chinese Hamster Cell ◽  
Coagulation Factor Viii ◽  
Recombinant Fviii

Серьезным осложнением, связанным с лечением гемофилии А, является развитие ингибиторов. В последние годы был проведён ряд исследований, посвящённых данной проблеме: RODIN, INSIGHT, FranceCoag, SIPPET и NuProtect. В данном обзоре суммируются основные результаты этих исследований. Согласно результатам рандомизированного исследования SIPPET, препараты плазматического фактора свертывания крови VIII (FVIII) обладают меньшей иммуногенностью, чем препараты рекомбинантного FVIII, синтезированного из клеточной линии китайских хомячков, что следует учитывать при выборе стратегии лечения. Согласно результатам исследования NuProtect, опубликованным в 2019 г., концентрат рекомбинантного FVIII, полученный из клеточной линии человека, демонстрирует профиль иммуногенности, сходный с таковым у препаратов плазматического FVIII. У ранее нелеченых пациентов с ненулевыми мутациями при применении симоктоког альфа не наблюдалось образования ингибиторов, также как и в случае применения препаратов плазматического FVIII в исследовании SIPPET. Inhibitor development is a serious complication associated with hemophilia A therapy. A number of studies have been carried out of this issue — RODIN, INSIGHT, FranceCoag, SIPPET, and NuProtect. This review summarizes the main results of these studies. According to the results of the SIPPET randomized trial, plasma-derived coagulation factor VIII (FVIII) products are less immunogenic than recombinant FVIII products synthesized from a Chinese hamster cell line; this fact should be taken into account in choosing a treatment strategy. According to the results of NuProtect study published in 2019, the concentrate of human cell line-derived recombinant FVIII demonstrates immunogenicity profi le similar to the one in plasma-derived FVIII products. Previously untreated patients with non-zero mutations receiving simoctocog alfa did not show development of inhibitors as well as in case of administration of plasma-derived FVIII products in SIPPET study.

scholarly journals The first recombinant human coagulation factor VIII of human origin: human cell line and manufacturing characteristics

2012 ◽  
Vol 89 (2) ◽  
pp. 165-176 ◽  
Author(s):  
Elisabeth Casademunt ◽  
Kristina Martinelle ◽  
Mats Jernberg ◽  
Stefan Winge ◽  
Maya Tiemeyer ◽  
...  
Keyword(s):  
Factor Viii ◽  
Cell Line ◽  
Human Cell ◽  
Coagulation Factor ◽  
Human Cell Line ◽  
Coagulation Factor Viii ◽  
Human Origin

scholarly journals Congenital hemophilia A with low activity of factor XII: a case report and literature review

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Baoyu Lei ◽  
Chuang Liang ◽  
Haiyan Feng
Keyword(s):  
Genetic Testing ◽  
Factor Viii ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation Factor Viii ◽  
Factor Xii ◽  
Fviii Activity ◽  
Recombinant Fviii ◽  
Low Activity

Abstract Background Congenital hemophilia A is a recessive inherited hemorrhagic disorder. According to the activity of functional coagulation factors, the severity of hemophilia A is divided into three levels: mild, moderate and severe. The first bleeding episode in severe and moderate congenital hemophilia A occurs mostly in early childhood and mainly involves soft tissue and joint bleeds. At present, there are limited reports on severe congenital hemophilia A with low factor XII (FXII) activity during the neonatal period. Case presentation A 13-day-old neonate was admitted to the hospital with hematoma near the joints of both upper arms. Coagulation tests showed he had low activity of factor VIII (FVIII) and FXII. He was diagnosed with congenital hemophilia A and treated with human coagulation factor VIII (recombinant FVIII). Although the hematoma became smaller, FVIII activity was only increased to a certain extent and FXII activity decreased gradually. Unfortunately, the child responded poorly to recombinant human coagulation factor VIII and his guardian rejected prophylactic inhibitors and genetic testing and refused further treatment. Three months later, the child developed intracranial hemorrhage (ICH) due to low FVIII activity. Conclusions In hemophilia A, the presence of FVIII inhibitors, drug concentration and testing are three important aspects that must be considered when FVIII activity does not reach the desired level. Early positive disease treatment and prophylaxis can decrease the frequency of bleeding and improve quality of life. We recommend that pregnant women with a family history of hemophilia A undergo early prenatal and neonatal genetic testing.

scholarly journals Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2925-2935 ◽  
Author(s):  
DD Pittman ◽  
EM Alderman ◽  
KN Tomkinson ◽  
JH Wang ◽  
AR Giles ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Specific Activity ◽  
Functional Characterization ◽  
Chinese Hamster ◽  
Coagulation Factor ◽  
Thrombin Activation ◽  
Recombinant Fviii

Abstract Coagulation factor VIII (FVIII) is a cofactor in the intrinsic pathway of blood coagulation for which deficiency results in the bleeding disorder hemophilia A. FVIII contains a domain structure of A1-A2-B-A3- C1-C2 of which the B domain is dispensable for procoagulant activity in vitro. In this report, we compare the properties of B-domain-deleted FVIII (residues 760 through 1639, designated LA-VIII) to wildtype recombinant FVIII. In transfected Chinese hamster ovary (CHO) cells, LA- VIII was expressed at a 10- to 20-fold greater level compared with wildtype FVIII. The specific activity of purified LA-VIII was indistinguishable from wild-type recombinant FVIII and both exhibited similar thrombin activation coefficients. Wildtype recombinant-derived FVIII and LA-VIII also displayed similar timecourses of thrombin activation and heavy chain cleavage. However, compared with wildtype recombinant-derived FVIII, the light chain of LA-VIII was cleaved fivefold more rapidly by thrombin. Addition of purified von Willebrand factor (vWF) did not alter the kinetics of thrombin cleavage or activation of either wildtype recombinant-derived FVIII or LA-VIII. The immunogenicity of LA-VIII was compared with wildtype FVIII in a novel model of neonatal tolerance induction in mice. The results did not detect any immunologic differences between wildtype FVIII and LA-VIII, suggesting that LA-VIII does not contain significant new epitopes that are absent in wildtype FVIII. LA-VIII was tolerated well on infusion into FVIII-deficient dogs and was able to correct the cuticle bleeding time similar to wildtype recombinant factor VIII. In vivo, LA-VIII was bound to canine vWF and exhibited a half-life similar to wildtype recombinant FVIII. These studies support that B-domain-deleted FVIII may be efficacious in treatment of hemophilia A in humans.

scholarly journals Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2925-2935 ◽  
Author(s):  
DD Pittman ◽  
EM Alderman ◽  
KN Tomkinson ◽  
JH Wang ◽  
AR Giles ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Specific Activity ◽  
Functional Characterization ◽  
Chinese Hamster ◽  
Coagulation Factor ◽  
Thrombin Activation ◽  
Recombinant Fviii

Coagulation factor VIII (FVIII) is a cofactor in the intrinsic pathway of blood coagulation for which deficiency results in the bleeding disorder hemophilia A. FVIII contains a domain structure of A1-A2-B-A3- C1-C2 of which the B domain is dispensable for procoagulant activity in vitro. In this report, we compare the properties of B-domain-deleted FVIII (residues 760 through 1639, designated LA-VIII) to wildtype recombinant FVIII. In transfected Chinese hamster ovary (CHO) cells, LA- VIII was expressed at a 10- to 20-fold greater level compared with wildtype FVIII. The specific activity of purified LA-VIII was indistinguishable from wild-type recombinant FVIII and both exhibited similar thrombin activation coefficients. Wildtype recombinant-derived FVIII and LA-VIII also displayed similar timecourses of thrombin activation and heavy chain cleavage. However, compared with wildtype recombinant-derived FVIII, the light chain of LA-VIII was cleaved fivefold more rapidly by thrombin. Addition of purified von Willebrand factor (vWF) did not alter the kinetics of thrombin cleavage or activation of either wildtype recombinant-derived FVIII or LA-VIII. The immunogenicity of LA-VIII was compared with wildtype FVIII in a novel model of neonatal tolerance induction in mice. The results did not detect any immunologic differences between wildtype FVIII and LA-VIII, suggesting that LA-VIII does not contain significant new epitopes that are absent in wildtype FVIII. LA-VIII was tolerated well on infusion into FVIII-deficient dogs and was able to correct the cuticle bleeding time similar to wildtype recombinant factor VIII. In vivo, LA-VIII was bound to canine vWF and exhibited a half-life similar to wildtype recombinant FVIII. These studies support that B-domain-deleted FVIII may be efficacious in treatment of hemophilia A in humans.

scholarly journals Potentiation of Thrombin Generation in Hemophilia A Plasma by Coagulation Factor VIII and Characterization of Antibody-Specific Inhibition

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48172 ◽  
Author(s):  
Bhavya S. Doshi ◽  
Bagirath Gangadharan ◽  
Christopher B. Doering ◽  
Shannon L. Meeks
Keyword(s):  
Factor Viii ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Specific Inhibition

scholarly journals Biological considerations of plasma-derived and recombinant factor VIII immunogenicity

Blood ◽  
2017 ◽  
Vol 129 (24) ◽  
pp. 3147-3154 ◽  
Author(s):  
Jesse Lai ◽  
Christine Hough ◽  
Julie Tarrant ◽  
David Lillicrap
Keyword(s):  
Risk Factors ◽  
Factor Viii ◽  
Environmental Variables ◽  
Neutralizing Antibodies ◽  
Genetic Factors ◽  
Hemophilia A ◽  
Clinical Care ◽  
Epidemiologic Studies ◽  
Inhibitor Development ◽  
Recombinant Fviii

Abstract In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.

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