Inhibitors in Hemophilia A: Advances in Elucidation of Inhibitory Mechanisms and in Inhibitor Management with Bypassing Agents

Natalya M Ananyeva; Timothy K Lee; Nisha Jain; Midori Shima; Evgueni L Saenko

doi:10.1055/s-0029-1245106

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2009; 35(8): 735-751
DOI: 10.1055/s-0029-1245106

Inhibitors in Hemophilia A: Advances in Elucidation of Inhibitory Mechanisms and in Inhibitor Management with Bypassing Agents

Natalya M. Ananyeva¹ , Timothy K. Lee¹ , Nisha Jain² , Midori Shima³ , Evgueni L. Saenko⁴

¹Laboratory of Hemostasis, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Rockville, Maryland
²Clinical Review Branch, Division of Hematology, Office of Blood Research and Review, CBER, FDA, Rockville, Maryland
³Department of Pediatrics, Nara Medical University, Nara, Japan
⁴Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow, Russia

Abstract

ABSTRACT

Development of inhibitory antibodies (inhibitors) to factor VIII (FVIII) is the most serious adverse event in replacement therapy of hemophilia A patients. The etiology and management of this condition remain major challenges for both researchers and clinicians. In the present review, we discuss recent advances in understanding the molecular mechanisms by which inhibitors inactivate FVIII and experimental approaches used for the mapping of inhibitor epitopes. We also present a comparative analysis of treatment of hemophilia A patients with inhibitors with currently available bypassing agents—activated prothrombin complex concentrate (FEIBA VH; Baxter Healthcare Corp., Westlake Village, CA) and recombinant activated factor VII (NovoSeven; Novo Nordisk, Princeton, NJ)—and describe some ongoing research programs aimed at developing new treatment options for these patients. Availability of sensitive and standardized laboratory assays that would assist in monitoring the effectiveness of bypass therapies is essential for designing customized treatment regimens and improvement in the management of health conditions of hemophilia patients with inhibitors.

KEYWORDS

Factor VIII - hemophilia A - inhibitor - epitope - bypass therapy

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Natalya M AnanyevaPh.D.

Laboratory of Hemostasis, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research

Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852

eMail: Natalya.Ananyeva@fda.hhs.gov