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Semin Thromb Hemost 2016; 42(05): 507-512
DOI: 10.1055/s-0036-1571309
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Emerging Issues in Diagnosis, Biology, and Inhibitor Risk in Mild Hemophilia A

Giancarlo Castaman
1   Department of Hearts, Lungs, and Vessels, Center for Bleeding Disorders, Careggi University Hospital, Firenze, Italy
,
Corien Eckhardt
2   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Alice van Velzen
2   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
,
Silvia Linari
1   Department of Hearts, Lungs, and Vessels, Center for Bleeding Disorders, Careggi University Hospital, Firenze, Italy
,
Karin Fijnvandraat
2   Department of Pediatric Hematology, Amsterdam Medical Center, Amsterdam, The Netherlands
› Author Affiliations
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Publication History

Publication Date:
05 May 2016 (online)

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Abstract

Mild hemophilia A (MHA) is an X-linked bleeding disorder defined by factor VIII (FVIII) levels between 5 and 40 U/dL. Diagnosis occurs later in life compared with severe or moderate disease. Although bleeding episodes are especially posttraumatic, their unexpected occurrence may be potentially life threatening if diagnosis is missed or delayed. Desmopressin is the treatment of choice for MHA since it is cheap and safe, but a significant proportion of cases do not attain FVIII postinfusion greater than 50 U/dL, which is considered a safe level for major surgery. Thus, replacement therapy may be needed and is usually successful in MHA, but recent data indicate that this can be associated with the occurrence of inhibitors against FVIII, as for severe hemophilia A. However, in contrast to severe or moderate hemophilia A, patients with MHA have a lifelong risk of inhibitor formation. Inhibitors may change the clinical phenotype dramatically, as the inhibitor frequently cross-reacts with the patient's endogenous FVIII, reducing the endogenous FVIII plasma levels below 1 U/dL. Specific F8 missense mutations predispose to inhibitor development. Inhibitors are frequently provoked by intensive treatment with therapeutic FVIII concentrates (more than 5 consecutive exposure days). Bleeding in inhibitor patients may be treated with desmopressin, high doses of FVIII concentrate or FVIII bypassing agents. Many inhibitors disappear over time when no FVIII concentrate is administered. However, this does not imply that a patient is tolerant and an anamnestic reaction may occur when treatment with FVIII concentrate is again necessary. To eradicate, an inhibitor different strategies may be used: watchful waiting, immunosuppression, or immune tolerance induction regimen.

Keywords

factor VIII - missense mutations - desmopressin - FVIII concentrates - inhibitors
 

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