Hemophilia A-From Basic Science to Clinical Practice

Abstract

This article summarizes achievements of basic research and their implementation in clinical treatment of one of the most common inherited bleeding disorders hemophilia A, which is caused by genetic deficiency of coagulation factor VIII (FVIII). We discuss the structure of FVIII, its major interactions in the intrinsic pathway of blood coagulation, and the catabolism of FVIII. We also discuss achievements in the contemporary clinical practice of treatment of hemophilia A. Replacement therapy has substantially improved by development of purification and virus inactivation procedures, allowing preparation of safe and effective therapeutic plasma-derived FVIII concentrates. We give special attention to the principles used in the development of contemporary recombinant FVIII products, which do not inherit a potential risk for viral or prion transmission. Development of FVIII inhibitory antibodies is the major complication of FVIII replacement therapy. We summarize the accumulated knowledge regarding epitopes of FVIII inhibitors and mechanisms by which they inactivate FVIII and discuss approaches to overcome the effects of inhibitors and to prevent their formation by induction of immunotolerance. We also analyze the main concepts and scientific priorities in the gene-therapeutic approach for treatment of hemophilia A.

Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia: Two Novel Mutations and Genotype-Phenotype Correlation

“…Since this is the most common type, it is frequently referred to as classic hemophilia. Hemophilia A is hereditary X-linked recessive, where heterozygous females transmit the affected gene and the disease phenotype presents almost exclusively in males [3,4]. However, several women, those carrying the disease, might have mild symptoms of this disease [5].…”

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

“…Deficiency or dysfunction of FVIII causes hemophilia A, a severe X-linked bleeding disorder (2). Infusion of recombinant FVIII or plasma-derived FVIII as a replacement is the first line of therapy for hemophilia A patients (3). Between 15% and 35% of severe hemophilia A patients will develop inhibitory responses to FVIII, presenting a major challenge in the clinical management of the disease (4).…”

Phosphatidylserine Containing Liposomes Reduce Immunogenicity of Recombinant Human Factor VIII (rFVIII) in a Murine Model of Hemophilia A**Karthik Ramani and Razvan D. Miclea contributed equally to the manuscript.

“…3 Replacement therapy with plasma-derived or recombinant human FVIII (rFVIII) is the most common therapy employed to control bleeding episodes. 4 A major complication in therapy is the induction of neutralizing antibodies against the exogenously administered protein, which occurs in approximately 15-30% of patients. [4][5][6] Although several approaches are employed clinically to manage patients manifesting inhibitor activity, 7,8 FVIII-neutralizing antibodies represent a major challenge in the management of the disease.…”