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"see table 11-15 for factor VIII and factor IX deficiency treatment guidelines In mg/dl.

cvWD, von Willebrand's disease. ^calculated in units of VWF: Rcof activity

"see table 11-15 for factor VIII and factor IX deficiency treatment guidelines In mg/dl.

cvWD, von Willebrand's disease. ^calculated in units of VWF: Rcof activity hemophilia, with factor IX deficiency accounting for the remainder. Both types occur with similar incidence among all races and in all parts of the world.

Hemophilia A Carrier Detection

Excessive lyonization may result in reduced FVIII levels in female carriers of hemophilia; hence, a reduced FVIII level can have utility in diagnosing the carrier state.

Direct gene mutation analysis: The FVIII common intron 22 inversion, resulting from an intrachromosomal recombination, is identifiable in 45% of severe hemophilia A patients. For the remaining 55% of severe hemophilia A patients as well as all mild and moderate hemophilia A patients, the molecular defects can usually be detected by efficient screening of all 26 FVIII exons and splice junctions. Therefore, direct gene mutation analysis is the most accurate test for carrier detection and prenatal diagnosis for severe hemophilia A. For rare patients in whom a precise mutation cannot be identified, intragenetic and extragenetic linkage analysis of DNA polymorphisms can be useful with up to 99.9% precision (when an affected male patient and his related family members are available).

When definitive diagnosis of the carrier state cannot be made, determination of the FVIII/vWF:Ag ratio (<1.0) can be used to detect 80% of hemophilia A carriers with 95% accuracy. Use of this methodology requires careful standardization of the laboratory performing the testing.

Hemophilia B Carrier Detection

Hemophilia B carriers have a wide range of FIX levels but, in a subset of cases, can be detected by the measurement of reduced plasma factor IX activity (in 60-70% of cases).

Direct gene mutation analysis: The factor IX gene is located centromeric to the factor VIII gene in the terminus of the long arm of the X chromosome. There is no linkage between the FVIII and FIX genes. The 34-kb FIX coding sequence comprises eight exons and encodes a 461-amino-acid precursor protein that is approximately one-third the size of the factor VIII cDNA. Because of the smaller gene size, FIX mutations can be identified in nearly all patients. Direct FIX mutation testing is available through DNA diagnostic laboratories, with linkage analysis used in those cases where the responsible mutation cannot be identified.

Prenatal Diagnosis

Prenatal diagnosis of hemophilia can be performed by either chorionic villus sampling (CVS) at 10-12 weeks' gestation or by amniocentesis after 15 weeks' gestation. If DNA analysis is not available or if a woman's carrier status cannot be determined, fetal blood sampling can be performed at 18-20 weeks' gestation for direct fetal factor VIII plasma activity level measurement. The normal fetus at 18-20 weeks' gestation has a very low FIX level, which an expert laboratory can distinguish from the virtual absence of FIX in a fetus with severe hemophilia B.

Maternal-fetal combined complication rates for amniocentesis and CVS are 0.5-1.0% and 1.0-2.0%, respectively. Fetal blood sampling is less available; the fetal loss rate for these procedures ranges from 1 to 6%.

Clinical Course of Hemophilia

Hemophilia should be suspected when unusual bleeding is encountered in a male patient. Clinical presentations of hemophilia A and hemophilia B are indistinguishable. The frequency and severity of bleeding in hemophilia are usually related to the plasma levels of factor VIII or IX (Table 11-11), although some genetic modifiers of hemophilia severity have been identified. The median age for first bleeding episode is 10 months, corresponding to the age at which the infant becomes mobile. Table 11-12 shows the common sites of hemorrhage in hemophilia. The incidence of severity and clinical manifestations of hemophilia are listed in Table 11-13.

Treatment (Factor Replacement Therapy)

Factor replacement therapy is the mainstay of hemophilia treatment. The degree of factor correction required to achieve hemostasis is largely determined by the site and nature of the particular bleeding episode. Commercially available products for replacement therapy are listed in Table 11-14. Commercially available FVIII products include high-purity recombinant preparations, highly purified plasma-derived concentrates (monoclonal/immunoaffinity purified), and intermediate-purity plasma-derived preparations. Available FIX products include recombinant FIX and plasma-derived high-purity FIX concentrate (coagulation FIX concentrate). Prothrombin complex concentrates, formerly a mainstay of hemophilia B treatment, are not utilized because of the risk of thrombotic complications associated with intensive treatment. Source plasma for all plasma-derived factor concentrates undergoes donor screening and nucleic acid testing for a variety of viral pathogens. In addition

Table 11-11. Relationship of Factor Levels to Severity of Clinical Manifestations of Hemophilia A and B

Percentage

Type factor VIII/IX Type of hemorrhage

Table 11-11. Relationship of Factor Levels to Severity of Clinical Manifestations of Hemophilia A and B

Percentage

Type factor VIII/IX Type of hemorrhage

Severe

<1

Spontaneous; hemarthroses and deep soft tissue hemorrhages

Moderate

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