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Violating the theory of single gene-single disorder: inhibitor development in hemophilia.

ABSTRACT: Hemophilia is clinically and genetically heterogeneous blood disorder with several known gene defects accounting for the diversity of disease phenotype and inhibitor production. Although increasing number of causative mutations have been reported, not much is known regarding the root cause of inhibitor development against infused blood clotting factors, which represents a major challenge in the treatment of disease. The variations in the severity and frequency of bleeding in hemophiliacs with same molecular defect, indicates the role of modifier genes in the pathogenesis of disease. Herein, we aim to review and summarise the literature over the past decade, to gain insight into what is critical for the development of inhibitors in hemophilia. Aside from potential mutations in factor VIII and IX, polymorphisms in various genes such as human leukocyte antigen-I (HLA-I), HLA-II, tumor necrosis factor-alpha, interleukin-10 and cytotoxic T-lymphocyte associated antigen-4, also tends to contribute to the development of inhibitors. Violating the theory of single gene-single disorder, new research indicates that inhibitor arise from a complex interplay of multiple genetic, immunological and environmental factors. With the revolutionary advances in whole genome sequencing, we propose a detailed genome wide study to identify the spectrum of genetic markers involved in the development of inhibitors for better diagnostics and therapeutics.

SUBMITTER: AlFadhli S

PROVIDER: S-EPMC4375149 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Violating the theory of single gene-single disorder: inhibitor development in hemophilia.

AlFadhli Suad S Nizam Rasheeba R

Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 20141120 2

Hemophilia is clinically and genetically heterogeneous blood disorder with several known gene defects accounting for the diversity of disease phenotype and inhibitor production. Although increasing number of causative mutations have been reported, not much is known regarding the root cause of inhibitor development against infused blood clotting factors, which represents a major challenge in the treatment of disease. The variations in the severity and frequency of bleeding in hemophiliacs with sa ...[more]

PMID: 25825553

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Project description:BackgroundDevelopment of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive 'on-demand' rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving 'on-demand' therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors.MethodsThe study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities.ResultsIn the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% (n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%).ConclusionsFactor VIII inhibitor prevalence in PWHA receiving 'on-demand' therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.

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Violating the theory of single gene-single disorder: inhibitor development in hemophilia.

Publications

Violating the theory of single gene-single disorder: inhibitor development in hemophilia.

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