Hemophilia A and B

Published on 04/03/2015 by admin

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Last modified 04/03/2015

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Chapter 60 Hemophilia A and B

Table 60-1 Factor VIII Mutant Genotype and Inhibitor Risk in Previously Untreated Hemophilia A Patients

Multidomain deletions ≈75%
Light chain nonsense mutns 30%-40%
Intron 22 inversion 20%-25%
Single domain deletions 15%-25%
Small non-A run insertions/deltns 15%-20%
Heavy chain nonsense mutns 10%-20%
Factor VIII missense mutns <10%
Small A run insertions/deltns <5%
Splicing mutns <5%

Table 60-2 Methods of Factor VIII Measurement

Hemophilia Carrier Detection and Prenatal Diagnosis

As an X-linked recessive trait, hemophilia most often manifests in males. However, females may be affected by the condition in two ways: through bleeding caused by low clotting factor levels and through transmission of the trait to later generations as a hemophilia carrier.

Women who are heterozygous carriers of a hemophilic mutation may have low levels of the implicated clotting factor. This depends on the ratio of inactivation of the hemophilic and normal X chromosomes, a random process that occurs early during embryonic development. If there is markedly skewed inactivation of the normal X chromosome, the plasma level of FVIII or FIX may be correspondingly reduced, and the carrier female may have evidence of a bleeding disorder. Thus FVIII or FIX levels should be determined in all potential carrier females before adolescence when they might first manifest with menorrhagia. A low plasma level of FVIII or FIX is predictive of the carrier state, and the lower the level, the more probable the carrier diagnosis.

Aside from using clotting factor levels to determine carrier status and bleeding risk, the most definitive approach to carrier diagnosis is to use molecular genetics to identify the causative FVIII or FIX mutation. Although carrier detection studies originally used analysis of linked polymorphisms to track mutant alleles, advances in sequencing technology now enable relatively easy access to direct mutation detection.

Ideally, carrier detection should be performed after puberty but before the woman is contemplating starting a family. In many countries, testing for the carrier status of genetic disease is prohibited before adolescence so that the girl can participate in discussions of testing options.

With current molecular genetic testing strategies, the results of mutation analyses are available within a few days in urgent circumstances. However, most often, results are returned within a few weeks.

Causative mutations in the FVIII or FIX genes are found in more than 95% of carriers. If a mutation is not found, it is possible that the mutation is deep within an intron or involves a distant transcriptional element.

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