C h a p t e r 1 2
Disorders of Hemostasis
273
concentrates from human plasma) administered at home
has reduced the typical musculoskeletal damage. It is
initiated when bleeding occurs or as prophylaxis with
repeated bleeding episodes. The newer recombinant
products and continuous-infusion pumps may allow
for prevention rather than therapy for hemorrhage. The
development of inhibitory antibodies to recombinant
factor VIII is still a major complication of treatment;
10% to 15% of treated persons produce high titers of
antibodies that bind to and inhibit factor VIII. The rate
of antibody production for plasma-derived products is
approximately the same.
Current factor VIII products (both plasma derived
and recombinant) are considered very safe as a result
of technological advances over the last two decades.
27
Until the mid-1980s when routine screening of blood
for HIV antibodies was instituted, thousands of patients
with hemophilia received plasma-derived factor VIII
that was contaminated with HIV, and many developed
AIDS. Effective donor screening and development of
purification and viral inactivation procedures now pro-
vide a safer product. A number of recombinant factor
VIII preparations are available. These products were
made with the use of blood-derived additives of human
or animal origin, such as albumin. These additives were
needed to keep the cells viable so they could produce the
factor VIII protein. With mild hemophilia A, the per-
son’s endogenously produced factor VIII can be released
by the administration of DDAVP.
27
In persons with
moderate to severe factor VIII deficiency, the stored lev-
els of factor VIII are insufficient, and DDAVP treatment
is ineffective.
The cloning of the factor VIII gene and progress in
gene delivery systems have led to the hope that hemo-
philia A may be cured by gene replacement therapy.
Carrier detection and prenatal diagnosis can now be
done by analysis of direct gene mutation or DNA link-
age studies.
Acquired Disorders
Coagulation factors II, V, VII, IX, X, XI, and XII; pro-
thrombin (II); and fibrinogen (I) are synthesized in the
liver. In liver disease, synthesis of these clotting factors
is reduced, and bleeding may result. Of the coagulation
factors synthesized in the liver, factors II, VII, IX, and
X and prothrombin require the presence of vitamin K
for normal activity. In vitamin K deficiency, the liver
produces the clotting factor, but in an inactive form.
Vitamin K is a fat-soluble vitamin that is continuously
being synthesized by intestinal bacteria. This means that
a deficiency in vitamin K is not likely to occur unless
intestinal synthesis is interrupted or absorption of the
vitamin is impaired. Vitamin K deficiency can occur in
the newborn infant before the establishment of the intes-
tinal flora; it can also occur as a result of treatment with
broad-spectrum antibiotics that destroy intestinal flora.
Because vitamin K is a fat-soluble vitamin, its absorp-
tion requires bile salts. Vitamin K deficiency may also
result from impaired fat absorption caused by liver or
gallbladder disease.
Bleeding Associated with Vascular
Disorders
Bleeding resulting from vascular disorders, sometimes
called
nonthrombocytopenic purpura,
is relatively com-
mon and results in mild bleeding disorders.
3,4
These dis-
orders may occur because of structurally weak vessel
walls or because of damage to vessels by inflammation
or immune responses. Most often they are character-
ized by easy bruising and the spontaneous appearance
of petechiae and purpura of the skin and mucous mem-
branes. In persons with bleeding disorders caused by
vascular defects, the platelet count and results of other
tests for coagulation factors are normal.
Among the vascular disorders that cause bleed-
ing are hemorrhagic telangiectasia, vitamin C defi-
ciency (scurvy), Cushing disease, and senile purpura.
Hemorrhagic telangiectasia is an uncommon autosomal
dominant disorder that is characterized by thin-walled,
dilated capillaries and arterioles. Vitamin C is a revers-
ible reducing agent that is an essential cofactor for the
hydroxylation of proline in collagen synthesis. A severe
vitamin C deficiency results in poor collagen synthesis
and failure of capillary cells to be cemented together
properly, which in turn causes a fragile vascular wall
(see Fig. 12-4). Cushing disease causes protein wasting
and loss of vessel tissue support because of excess cor-
tisol (see Chapter 32). Senile purpura (i.e., bruising in
elderly persons) is caused by impaired collagen synthesis
due to the aging process.
Disseminated Intravascular
Coagulation
Disseminated intravascular coagulation (DIC) is a paradox
in the hemostatic sequence characterized by widespread
coagulation and bleeding.
28–31
It is not a primary disease but
a complication of many different disorders. Disseminated
intravascular coagulation begins withmassive activation of
the coagulation sequence, which leads to fibrin deposition
andformationofthrombiinthemicrocirculationofthebody
(Fig. 12-5). The widespread deposition of fibrin leads to
tissue ischemia and hemolytic anemia from fragmentation
of red cells as they squeeze through the narrowed micro-
vasculature. As a consequence of the thrombotic process,
there is consumption of platelets and coagulation factors
and the activation of plasminogen that leads to a hemor-
rhagic diathesis.
The disorder can be initiated by activation of the
intrinsic or extrinsic pathway, or both. Activation
through the extrinsic pathway occurs with liberation of
tissue factors and is associated with obstetric complica-
tions, trauma, bacterial sepsis, and cancer. The intrinsic
pathway may be activated through extensive endothe-
lial damage, with activation of factor XII. Endothelial
damage may be caused by viruses, infections, immune
mechanisms, stasis of blood, or temperature extremes.
Impaired anticoagulation pathways are also associ-
ated with reduced levels of antithrombin and the pro-
tein C anticoagulant system in DIC. There is increasing
