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Semin Thromb Hemost 2018; 44(06): 568-577
DOI: 10.1055/s-0037-1621717
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Inhibitors in Nonsevere Hemophilia A: What Is Known and Searching for the Unknown

Amal Abdi
1   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Silvia Linari
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
,
Lisa Pieri
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
,
Jan Voorberg
3   Sanquin, Amsterdam, The Netherlands
,
Karin Fijnvandraat
1   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Giancarlo Castaman
2   Department of Oncology, Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, Italy
› Author Affiliations
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Publication History

Publication Date:
13 February 2018 (online)

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Abstract

Nonsevere hemophilia A (NSHA) is an inherited X-linked bleeding disorder, caused by mutations of the F8 gene, leading to decreases of clotting factor VIII (FVIII) levels to 1 to 40 IU/dL. Desmopressin is the first therapeutic option for NSHA, but 40 to 50% of patients fail to attain adequate postinfusion FVIII levels. Thus, in these cases, FVIII concentrates remain the mainstay of treatment. The development of neutralizing FVIII antibodies (inhibitors) is a major challenge with replacement therapy. In contrast to severe disease, NSHA patients have a lifelong risk of inhibitor development. Recent data indicate that inhibitors are associated with a deterioration of clinical outcome, illustrated by an increase in bleeding and mortality rate. F8 genotype is an important risk factor for inhibitor occurrence together with surgical interventions and a high dose of FVIII concentrate. Adequate prevention and treatment of inhibitors in NSHA patients is limited by a lack of understanding of the underlying immunological mechanisms. Elucidation of the immunology driving inhibitor development is required to identify high-risk patients, to understand the association between clinical risk factors and inhibitor occurrence, and to provide the opportunity to develop new preventive and therapeutic strategies.

Keywords

nonsevere hemophilia A - diagnosis - treatment - inhibitor development - immunological characteristics