C h a p t e r 1 2
Disorders of Hemostasis
271
ITP do well without treatment. Corticosteroids are
used as initial therapy; other effective initial treatment
includes intravenous immune globulin. However, this
treatment is expensive and the beneficial effect may last
only one to two weeks. Because the spleen is the major
site of antibody formation and platelet destruction, sple-
nectomy is the traditional second-line treatment for per-
sons who relapse or do not respond to medications.
18
Immunosuppressive therapy (i.e., azathioprine or cyclo-
phosphamide) may be used in patients who are refrac-
tory to other forms of treatment.
Drug-Induced Thrombocytopenia.
Some drugs, such
as quinine, quinidine, and certain sulfa-containing anti-
biotics, may induce thrombocytopenia.
19
These drugs
act as haptens to induce an antigen–antibody response
and formation of immune complexes that cause platelet
destruction by complement-mediated lysis (see Chapter
15). In persons with drug-associated thrombocytopenia,
there is a fall in platelet count 7 or more days after ini-
tiating therapy with a given drug for the first time (i.e.,
the needed to mount an immune response) or 2 to 3 days
after resuming therapy with the same drug. The platelet
count rises rapidly after the drug is discontinued.
The anticoagulant drug heparin has been increasingly
implicated in thrombocytopenia and, paradoxically,
in thrombosis. The complications typically occur five
days after the start of therapy and result from heparin-
dependent antiplatelet antibodies that cause aggregation
of platelets and their removal from the circulation. The
antibodies often bind to vessel walls, causing complica-
tions such as deep vein thrombosis, pulmonary embo-
lism, myocardial infarction, and stroke.
20
The treatment
of heparin-induced thrombocytopenia (HIT) requires
the immediate discontinuation of heparin therapy and
the use of alternative anticoagulants (i.e., argatroban,
fondaparinux) to prevent thrombosis recurrence. The
use of low–molecular-weight heparin appears to have
reduced the incidence of HIT, though there have only
been a limited number of large, randomized, controlled
studies.
Thrombotic Microangiopathies.
The term
throm-
botic microangiopathies
encompasses a spectrum of
clinical syndromes that include thrombotic thrombocy-
topenic purpura (TTP) and hemolytic-uremic syndrome
(HUS).
3
As originally described, TTP is associated with
a combination of manifestations that includes fever,
thrombocytopenia, microangiopathic hemolytic ane-
mia, renal failure, and transient neurologic abnormali-
ties. Hemolytic-uremic syndrome is also associated with
microangiopathic hemolytic anemia and thrombocy-
topenia, but it is distinguished from TTP by the domi-
nance of acute renal failure and absence of neurologic
manifestations. Fundamental to both conditions is the
widespread formation of hyaline thrombi in the micro-
circulation that are composed primarily of dense aggre-
gates of platelets surrounded by fibrin. The consumption
of platelets leads to thrombocytopenia, and the narrow-
ing of the blood vessels by the platelet-rich thrombi
results in the microangiopathic hemolytic anemia.
The pathogenesis of TTP is elusive but likely results
from introduction of platelet-aggregating substances
into the circulation. The underlying cause of many cases
is the deficiency of an enzyme (ADAMTS 13, formerly
known as vWF-cleaving protease) that degrades very
high–molecular–weight multimers of vWF, allowing
them to accumulate and cause platelet aggregation and
adhesion to the endothelium.
3,4
The enzyme deficiency
may be inherited or acquired as a result of antibody
directed against the enzyme. Although TTP usually
occurs in previously healthy persons, it may also com-
plicate collagen vascular diseases (rheumatoid arthri-
tis and systemic lupus erythematosus), drug-induced
hypersensitivities, cancer chemotherapy, bone marrow
transplantation, infections such as HIV, and pregnancy.
4
Thrombotic thrombocytopenic purpura occurs at
virtually every age, but is most common in women in
their fourth or fifth decades. It can be chronic and recur-
rent, but more frequently the onset is abrupt and the
outcome may be fatal. Widespread vascular occlusions
result from thrombi in the arterioles and capillaries of
many organs, including the heart, brain, and kidneys.
The clinical manifestations include purpura, petechiae,
vaginal bleeding, and neurologic symptoms ranging
from headache to seizures and altered consciousness.
Anemia is universal and may be marked. About half of
patients have azotemia due to renal failure.
4
Emergency treatment for TTP includes
plasmapher-
esis,
a procedure that involves removal of plasma from
withdrawn blood and replacement with fresh-frozen
plasma. Plasma infusion provides the deficient enzyme.
With plasmapheresis and plasma infusion treatment,
there is a complete recovery in 80% of cases.
4
Although clinically similar to TTP, there is no under-
lying enzyme deficiency in HUS because ADAMTS 13
levels are normal. HUS in children and the elderly usu-
ally occurs following infectious gastroenteritis caused
by
Escherichia coli
O157:H7
14
(see Chapter 29). The
organism elaborates a toxin that damages endothelial
cells, which initiates platelet activation and aggregation.
Affected individuals often present with bloody diarrhea,
which is followed a few days later by HUS. With sup-
portive care and plasma exchange, recovery is possible,
but irreversible renal damage and death can occur in
severe cases.
Impaired Platelet Function
Impaired platelet function (also called
thrombocyto-
pathia
) may result from inherited disorders of adhesion
(e.g., von Willebrand disease) or acquired defects caused
by drugs, disease, or surgery involving extracorporeal
circulation (i.e., cardiopulmonary bypass). Defective
platelet function is also common in uremia, presumably
because of non-eliminated waste products.
The use of aspirin and other nonsteroidal anti-
inflammatory drugs (NSAIDs) is the most common
cause of platelet dysfunction. Aspirin produces irrevers-
ible acetylation of platelet cyclooxygenase activity, and
consequently the synthesis of TXA
2
, which is required
for platelet aggregation. The effect of aspirin on platelet
