272
U N I T 3
Hematopoietic Function
aggregation lasts for the life of the platelet—approxi-
mately 8 or 9 days. In contrast to the effects of aspirin,
the inhibition of cyclooxygenase by other NSAIDs is
reversible and lasts only for the duration of drug action.
Aspirin (81 mg daily) commonly is used to prevent for-
mation of arterial thrombi and thus reduce the risk of
cardiovascular (i.e., myocardial infarction) or cerebro-
vascular (i.e., stroke) accidents.
Coagulation Disorders
Blood coagulation defects can result from deficiencies or
impaired function of one or more of the clotting factors,
including vWF. Deficiencies can arise because of inher-
ited disease or because of defective synthesis or increased
consumption of the clotting factors. Bleeding resulting
from clotting factor deficiencies typically occurs after
injury or trauma. Large bruises (ecchymoses), hemato-
mas, and prolonged bleeding into the gastrointestinal or
urinary tracts or joints are common.
Inherited Disorders
Hemophilia A and von Willebrand disease are two of
the most common inherited disorders of bleeding.
21,22
Hemophilia A (factor VIII deficiency) affects 1 in 5000
male live births and von Willebrand disease about 1 in
1000 persons.
21
Hemophilia B (Factor IX deficiency) is
clinically similar to hemophilia A and affects approxi-
mately 1 in 20,000 persons, accounting for 15% of peo-
ple with hemophilia.
4
Hemophilia A and von Willebrand disease are caused
by defects involving the factor VIII–vWF complex. Von
Willebrand factor, which is synthesized by the endothe-
lium and megakaryocytes, is required for platelet adhe-
sion to the subendothelial matrix of the blood vessel. It
also serves as the carrier for factor VIII and it is impor-
tant for the stability of factor VIII in the circulation by
preventing its proteolysis. Factor VIII coagulant protein,
the functional portion of factor VIII, is produced by the
liver and endothelial cells. Thus, factor VIII and vWF,
synthesized separately, come together and circulate in
the plasma as a unit that serves to promote clotting and
adhesion of platelets to the vessel wall.
Von Willebrand Disease.
Von Willebrand disease is a
relatively common hereditary bleeding disorder charac-
terized by a deficiency or defect in vWF. It affects both
men and women and is typically diagnosed in adult-
hood.
23,24
In most cases, it is transmitted as an autosomal
dominant disorder, but several rare autosomal recessive
variants have been identified.
As many as 20 variants of von Willebrand disease
have been described.
4
These variants can be grouped
into two categories: types 1 and 3, which are associ-
ated with reduced levels of vWF; and type 2, which is
characterized by defects in vWF.
4
Type 1, an autosomal
dominant disorder, accounts for approximately 75% of
cases and is relatively mild. Type 2, also an autosomal
dominant disorder, accounts for about 20% of cases and
is associated with mild to moderate bleeding. Type 3,
which is a relatively rare autosomal recessive disorder, is
associated with extremely low levels of functional vWF
and correspondingly severe clinical manifestations.
Persons with von Willebrand disease have a com-
pound defect involving platelet function and the
coagulation pathway. Clinical manifestations include
spontaneous bleeding from the nose, mouth, and gas-
trointestinal tract; excessive menstrual flow; and a pro-
longed bleeding time in the presence of a normal platelet
count. Most cases (i.e., types 1 and 2) are mild and the
disorder is diagnosed when surgery or dental extraction
results in prolonged bleeding. In severe cases (i.e., type 3),
life-threatening gastrointestinal bleeding and joint hem-
orrhage may be similar to that seen in hemophilia.
The bleeding associated with von Willebrand disease
is usually mild, and no treatment is routinely admin-
istered other than avoidance of aspirin. Desmopressin
acetate (DDAVP), a synthetic analog of the hormone
vasopressin, is used in the treatment of type 1 von
Willebrand disease and for establishing hemostasis dur-
ing surgical or dental procedures.
22,23
DDAVP stimulates
the endothelial cells to release stored vWF and plasmin-
ogen activator. The drug is available as an intranasal
spray. A vWF-containing factor VIII concentrate may be
used for treatment of persons with excessive bleeding.
21
Hemophilia A.
Hemophilia A is an X-linked recessive
disorder that primarily affects males.
3,4,22,24,25
Although
it is a hereditary disorder, there is no family history of
the disorder in approximately 30% of newly diagnosed
cases, suggesting that it has arisen as a new mutation
in the factor VIII gene. Approximately 90% of persons
with hemophilia produce insufficient quantities of the
factor and 10% produce a defective form. The per-
centage of normal factor VIII activity in the circulation
depends on the genetic defect and determines the sever-
ity of hemophilia (i.e., 6% to 30% in mild hemophilia,
2% to 5% in moderate hemophilia, and 1% or less in
severe forms of hemophilia). In mild or moderate forms
of the disease, bleeding usually does not occur unless
there is a local lesion or trauma such as surgery or a den-
tal procedure. The mild disorder may not be detected
in childhood. In severe hemophilia, bleeding usually
occurs in childhood (e.g., it may be noticed at the time
of circumcision) and is spontaneous and severe, often
occurring several times a month.
Characteristically, bleeding occurs in soft tissues, the
gastrointestinal tract, and the hip, knee, elbow, and ankle
joints. Spontaneous joint bleeding usually begins when a
child begins to walk, with the target joint often prone to
recurrent incidences. The bleeding causes inflammation
of the synovium, with acute pain and swelling. Without
proper treatment, chronic bleeding and inflammation
cause joint fibrosis and contractures, resulting in major
disability. Muscle hematomas may be present in 30%
of episodes, and intracranial hemorrhage, although
uncommon, is an important cause of death.
22,26
The prevention of trauma is important in per-
sons with hemophilia. Aspirin and other NSAIDs that
affect platelet function should be avoided. Factor VIII
replacement therapy (either recombinant or heat-treated
