W Keith Hoots, MD
Amy D Shapiro, MD
Lawrence LK Leung, MD
Donald H Mahoney, Jr, MD
Stephen A Landaw, MD, PhD
Last literature review version 18.3: septiembre 2010 | This topic last updated: julio 2, 2009 (More)
INTRODUCTION — The hemophilias are a group of related bleeding disorders that mostcommonly are inherited. Inherited bleeding disorders include abnormalities of coagulation factors and platelet function; the most common of these is von Willebrand disease. However, when the term "hemophilia" is used, it most often refers to the following two disorders:
• Factor VIII deficiency (hemophilia A)
• Factor IX deficiency (hemophilia B, Christmas disease)
The clinical manifestationsand diagnosis of these conditions will be reviewed here. Therapy with replacement factors and the development of inhibitors are discussed separately. (See "Treatment of hemophilia" and "Factor VIII and factor IX inhibitors in patients with hemophilia".)
CLINICAL MANIFESTATIONS — Hemophilia A and B are X-linked recessive diseases. They exhibit a range of clinical severity that correlates wellwith assayed factor levels. Severe disease is defined as 5 percent of normal are defined as moderate and mild disease, respectively [1,2]. Males within a family have the same level of deficiency because they share the same genetic defect.
The combined incidence of hemophilia A and B is 1 in 5000 live male births. Approximately 80 percent have hemophilia A, two-thirds of whom have severe disease. Incontrast, almost one-half of individuals with hemophilia B (which occurs in 1 in 25,000 to 1 in 30,000 births) have factor IX levels above 1 percent (ie, moderate or mild disease). Hemophilia A and B of comparable severity bleed with similar frequency .
Some patients with severe disease have a milder clinical course :
• The Leyden phenotype of hemophilia B is characterized by severehemophilia in childhood that becomes mild after puberty. The mutation at nucleotide-20 in the promoter region in this disorder disrupts the hepatocyte nuclear factor-4 (HNF-4) binding site but not the overlapping site for an androgen response element, which may explain the recovery at puberty [5-7]. These patients also may have less disruption of the HNF-4 binding site .
• Coinheritance ofthe factor V Leiden mutation and other prothrombotic markers occurs in a small proportion of patients with severe hemophilia A [8,9]. The presence of such prothrombotic conditions partially counteracts the bleeding tendency of hemophilia, resulting in fewer bleeding episodes and a later onset of first bleeding [9-11]. (See "Activated protein C resistance and factor V Leiden" and 'Initialpresentation' below.)
Bleeding may occur anywhere in patients with hemophilia. The most common sites are into joints and muscles and from the gastrointestinal tract. Approximately 80 percent of hemorrhage occurs in the joints; the ankles are most commonly affected in children, and the knees, elbows, and ankles in adolescents and adults . Spontaneous hemarthroses are so characteristic of severehemophilia as to be almost diagnostic. This pattern is different from the mucosal and cutaneous bleeding characteristic of platelet dysfunction or von Willebrand disease (table 1). Mucosal bleeding may manifest as epistaxis and gingival bleeding, and bullous hemorrhages may appear on the buccal mucosa. (See "Approach to the adult patient with a bleeding diathesis".)
The settings in which bleeding occursvary with the severity of the disease. Bleeding occurs only in response to injury/trauma or surgery in patients with mild hemophilia [2,13], to intercurrent injury or surgery in moderate hemophilia, and spontaneously and at an early age in severe hemophilia. Female carriers of the disease have variable factor levels; bleeding does not occur in those with near normal levels, but those with less...