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Hemophilia is a bleeding disorder resulting from a congenital deficiency in either factor VIII or factor IX. Personal and family history of bleeding is an important tool in the postnatal diagnosis of hemophilia; however, 20% to 30% of individuals with hemophilia have no previously affected family members. Furthermore, persons with mild disease may not manifest the classic symptoms of hemophilic bleeding. Importantly, neither symptoms nor family history distinguish hemophilia A from hemophilia B. The postnatal diagnosis of hemophilia most reliably is made, therefore, by direct assay of plasma factor VIII or IX activity levels. Factor VIII activity is comparably measured by any of three assays using either clot-based or chromogenic substrate methodology. von Willebrand factor assays are used to further distinguish factor VIII deficiency from von Willebrand disease. Factor IX activity is measured using a clot detection assay. Factors VIII and IX activity levels are generally reported in units (U/mL), with 1 U/mL corresponding to 100% of the factor found in 1 mL of normal plasma. Normal plasma activity levels usually range between 0.5 U/mL and 1.5 U/mL (50%-150%). These measurements of factor activity now define the three levels of severity that make up the spectrum of hemophilia, hemopilia, hemofilia, hemaphilia
Carrier Detection and Prenatal DiagnosisThe hemophilia gene mutation is thought to have originated at least 65 million years ago and is
In humans, hemophilia A is the third most common X-linked disorder, occurring with an incidence of approximately 1 in 5000 male births. Cloned in 1984 and weighing in at 186 kilobases (kb), the affected hemophilia A patients but in only 50% to 60% of severely affected pedigrees.
Until recently, because of the great variability in the hemophilia A gene mutation, carrier detection was largely performed using intragenic and extragenic linkage analysis of DNA polymorphisms. These
In 1993, however, a major genetic collaboration identified an inversion in the factor VIII gene at intron 22 resulting from an intrachromosomal recombination. This mutation alone accounts for 40% to
Hemophilia B occurs in the general population at one-fourth to one-sixth the incidence of hemophilia A. The factor IX gene, cloned and completely sequenced in 1982, is 34 kb and located centromeric to the factor VIII gene in the terminus of the long arm of the X chromosome. No link
When carrier detection in both hemophilias A and B is possible on the basis of either linkage studies or direct gene-mutation analysis, prenatal diagnosis can be performed at most high-risk obstetric
Maternal-fetal combined complication rates for amniocentesis and CVS are 0.5% to 1.0% and 1.0% to 2.0%, respectively, and should be discussed in routine prenatal genetic counseling performed
The routine use of gene-based diagnosis in patients with hemophilias A and B will become more common as techniques are adapted to routine diagnostic laboratories and made more available to treatment centers. When used in this way, gene-based diagnosis may have broad applicability in
The mainstay of successful hemophilia therapy for either treatment or prevention of acute hemorrhage is prompt and sufficient intravenous replacement of factor VIII or IX to hemostatic plasma levels. Early treatment, at the first onset of symptoms, limits both the amount of the bleeding and the extent of the ensuing tissue damage.
State-of-the-art replacement products are made from either plasma-derived or recombinant proteins. All such plasma-derived products have similar hemostatic efficacy and undergo a viral attenuation step
Single-donor-cryoprecipitate, derived from plasmapheresis of a DDAVP-treated plasmapheresis donor with negative viral serology, is a potential source of factor VIII suitable for a
Recombinant factor VIII has never been linked to transmission of hepatitis C or HIV-1, though it contains human albumin. In the late 1990s, concern has turned to the potential risk of the albumin in plasma for transmission of Creutzfeldt-Jacob disease (CJD), or "new-variant" CJD, the human syndrome linked to mad-cow disease in Great Britain. It should be stressed that albumin is thought to
The therapeutic menu for factor IX has improved substantially over the past few years with the advent of monoclonal, and more recently, recombinant factor. Again, selection of factor IX-containing products generally is based on issues of cost and product purity. First, cost between low and high
Ancillary Therapy
DDAVP, 1-deamino 8-D arginine vasopressin, stimulates a transient fourfold increase in plasma factor VIII levels, although its mechanism of action still has not been completely elucidated. Therefore, it provides an effective alternative therapy for less severe hemorrhage in most patients with mild
Antifibrinolytic therapy is used to stabilize a clot by inhibiting the normal process of clot lysis by the fibrinolytic system. It is, therefore, very useful ancillary treatment in patients with hemorrhagic disorders. These agents provide important adjunctive therapy for the prevention or treatment of oral hemorrhage because saliva is a rich source of fibrinolytic enzymes. Two drugs are available: (1) epsilon aminocaproic acid (EACA) (Amicar) and (2) tranexamic acid (Cyklokapron). EACA is
Both hemophilias A and B have been "cured" by orthotopic liver transplantation performed in the 1980s for transfusion-related liver failure. Since the factor VIII and IX genes were cloned, the hemophilias have been considered to be genetic diseases that are among the most amenable to gene therapy because of: (1) the lack of requirement for tissue-specific expression; (2) the absence of