Inherited bleeding disorders are
a heterogeneous group of conditions that lead to excessive hemorrhage.
The disorders have distinct inheritance patterns, clinical bleeding
symptoms, and laboratory abnormalities. Therefore, the history and
physical examination are key to guiding appropriate laboratory testing
Hemophilia A, or classical hemophilia, results from congenital
deficiency or absence of circulating factor VIII (FVIII). It is
an X-linked recessive disorder with an incidence of approximately 1:5000
male births.1 Hemophilia B is also known as Christmas
disease after Stephen Christmas who was the first child described
with the disorder.2 It results from a congenital
deficiency or absence of factor IX (FIX). It is an X-linked recessive disorder
with an incidence of approximately 1:25,000 male births.1 Hemophilia
C is an autosomal recessive disorder resulting in decreased amounts
of circulating factor XI. It affects 1 in 100,000 people.
Factor VIII is a plasma glycoproteinconsisting of 6 domains,
A1-A2-B-A3-C1-C2 (eFig. 436.1) .3 The
encoding gene is found on the long arm of the X chromosome (Xq28).The
mature protein is a heterodimer with a light chain consisting of
domains A3-C1-C2 and a heavy chain composed of the domains A1-A2-B. The
majority of FVIII is thought to be synthesized in liver endothelial
cells. Upon release into the circulation, it is immediately noncovalently linked
to von Willebrand factor (vWF). This prevents enzymatic degradation
of FVIII until it is needed during coagulation. As illustrated in eFigure 436.2, during coagulation tissue
factor combines with FVIIa at the site of injury. This complex activates
FX and FIX, leading to conversion of prothrombin to thrombin. The
initial thrombin cleavage of the FVIII light chain causes FVIII
to be released into the circulation and then activated to FVIIIa
by further thrombin-mediated proteolysis. FVIIIa and FIXa then act
as cofactors on a phospholipid surface (typically a platelet) during
activation of factor X, V, and ultimately, thrombin (eFig.
436.2).4 Many molecular defects have been
described in the pathology of hemophilia A. These include gross gene
rearrangements of the DNA sequence, single gene rearrangements,
deletions of some or all of the gene sequence, and DNA insertions.
A continually updated list of mutations leading to hemophilia A
can be found at http://europium.csc.mrc.ac.uk.
Domain structure of factor VIII. Factor VIII consists
of 3 A domains, 1 B domain, and 2 C domains that are linked by an activation
Factor IX is a vitamin K–dependent serine protease believed
to be synthesized in the liver and released into the circulation
in its inactive form. The gene is 33 kilobases long on the end of
the X chromosome (Xq27).3 During coagulation, tissue
factor and FVII activate ...