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Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.
This article was published in the following journal.
Name: PloS one
Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of autoantibodies against coagulation factor VIII (FVIII). The mortality rate remains high. International rec...
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Altered levels of factor (F)VIII, prothrombin, or antithrombin have been associated with an increased risk for venous thromboembolism (VTE). However, the exact molecular mechanism by which these alter...
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Hemophilia A is a genetic deficiency of factor VIII that causes blood to clot too slowly. The disease is classified based on how much factor VIII is in the blood. People with mild or moder...
This international study will identify genetic factors that may influence the development of inhibitory antibodies in patients with hemophilia A after treatment with factor VIII. Bleeding ...
Commercial one and two-stage factor VIII assays may not detect some clinically significant inhibitor antibodies. The purpose of the proposed study is to standardize and validate a platelet...
Haemophilia is a rare and serious congenital defect of blood coagulation due to a genetic mutation on a sexual chromosome. It affects quasi-essentially the men and it is responsible for bl...
The study start on January 18, 2017. The Severe(FⅧ
Blood-coagulation factor VIII. Antihemophilic factor that is part of the factor VIII/von Willebrand factor complex. Factor VIII is produced in the liver and acts in the intrinsic pathway of blood coagulation. It serves as a cofactor in factor X activation and this action is markedly enhanced by small amounts of thrombin.
Activated form of factor VIII. The B-domain of factor VIII is proteolytically cleaved by thrombin to form factor VIIIa. Factor VIIIa exists as a non-covalent dimer in a metal-linked (probably calcium) complex and functions as a cofactor in the enzymatic activation of factor X by factor IXa. Factor VIIIa is similar in structure and generation to factor Va.
Telephone surveys are conducted to monitor prevalence of the major behavioral risks among adults associated with premature MORBIDITY and MORTALITY. The data collected is in regard to actual behaviors, rather than on attitudes or knowledge. The Centers for Disease Control and Prevention (CDC) established the Behavioral Risk Factor Surveillance System (BRFSS) in 1984.
Storage-stable blood coagulation factor acting in the intrinsic pathway. Its activated form, IXa, forms a complex with factor VIII and calcium on platelet factor 3 to activate factor X to Xa. Deficiency of factor IX results in HEMOPHILIA B (Christmas Disease).
A non-fibrillar collagen originally found in DESCEMET MEMBRANE. It is expressed in endothelial cell layers and in tissues undergoing active remodeling. It is heterotrimer comprised of alpha1(VIII) and alpha2(VIII) chains.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...