268
U N I T 3
Hematopoietic Function
include an increase in platelet count and disturbances
in blood flow, damage to the vascular endothelium, and
increased sensitivity of platelets to factors that cause
adhesiveness and aggregation.
The term
thrombocytosis
is used to describe eleva-
tions in the platelet count above 1,000,000/
μ
L.
9
An
increase in platelet count can occur as a reactive dis-
order associated with iron-deficiency anemia, especially
in children; splenectomy; cancer; and chronic inflamma-
tory conditions such as rheumatoid arthritis and Crohn
disease. Usually the only clinically apparent signs are
those of the underlying disease. Myeloproliferative dis-
orders such as polycythemia vera (see Chapter 14) pro-
duce excess platelets that may predispose to thrombosis
or, paradoxically, bleeding when the rapidly produced
platelets are defective.
Atherosclerotic plaques disturb blood flow, causing
endothelial damage and promoting platelet adherence.
Platelets adhere to the vessel wall, release growth fac-
tors, cause proliferation of smooth muscle, and thereby
contribute to the development of atherosclerosis (see
Chapter 18). Smoking, elevated levels of blood lipids
and cholesterol, hemodynamic stress, and diabetes mel-
litus predispose to vessel damage, platelet adherence,
and eventual thrombosis.
Increased Clotting Activity
Thrombus formation due to activation of the coagu-
lation system can result from primary (genetic) or
secondary (acquired) disorders affecting the coagula-
tion components of the blood clotting process (i.e., an
increase in procoagulation factors or a decrease in anti-
coagulation factors).
Inherited Disorders
Of the inherited causes of hypercoagulability, mutations
in the factor V and prothrombin genes are the most
common.
4,10
In persons with inherited defects in factor
V, the mutant factor Va cannot be inactivated by protein
C; as a result, an important antithrombotic counterreg-
ulatory mechanism is lost. Approximately 2% to 5% of
Caucasians carry a specific factor V mutation (referred
to as the
Leiden mutation,
because of the Dutch city
where it was first discovered).
3
The defect predisposes to
venous thrombosis, and among persons with recurrent
deep vein thrombosis, the frequency of the mutation
may be as high as 60%.
3
It is one of the most common
causes of primary and recurrent thromboembolism in
pregnancy and is also associated with abruptio placen-
tae (premature placental separation) and fetal growth
disturbance.
10
A single nucleotide change in the prothrombin gene,
which affects 1% to 2% of the population, is associated
with elevated prothrombin levels and an almost three-
fold increase in venous thromboses.
4
Another hereditary
defect results in high circulating levels of homocyste-
ine, which predisposes to venous and arterial thrombo-
sis by activating platelets and altering antithrombotic
mechanisms.
4
Acquired Disorders
Unlike the hereditary disorders, multiple conditions
often predispose persons to acquired or secondary
thrombotic disorders. Stasis of blood and accumulation
of platelets and activated clotting factors are common in
situations such as with prolonged bed rest and immobil-
ity. Hyperviscosity syndromes (e.g., polycythemia) and
deformed red blood cells in sickle cell disease increase
the resistance to flow and cause small vessel stasis.
Hypercoagulability is associated with oral contraceptive
use and the hyperestrogenic state of pregnancy, prob-
ably related to the increased synthesis of coagulation
factors and reduced synthesis of antithrombin III.
11
The
incidence of stroke, thromboemboli, and myocardial
infarction is greater in women who use oral contra-
ceptives, particularly those older than 35 years of age
and those who smoke tobacco. In disseminated cancer,
release of procoagulant tumor products predisposes to
thrombosis. Smoking and obesity promote hypercoagu-
lability for unknown reasons.
Antiphospholipid Syndrome.
Another cause of
increased venous and arterial thrombosis is the
antiphospholipid syndrome
. This condition is associ-
ated with a family of autoantibodies directed against
several negatively charged phospholipids, causing
an increase in coagulation activity. It is unclear how
antiphospholipid antibodies lead to hypercoagulability,
but possible explanations include direct platelet activa-
tion, endothelial cell activation or injury, or interfer-
ence with the phospholipid-binding proteins involved
in the regulation of blood coagulation (e.g., tissue fac-
tor, prothrombin, antithrombin III, and protein C).
12–14
Common features of the syndrome include recurrent
CHART 12-1
Conditions Associated with
Hypercoagulability States
Increased Platelet Function
Increased platelet numbers
Reactive disorder (iron-deficiency anemia, splenec
tomy, cancer, chronic inflammatory conditions)
Myeloproliferative disorders (polycythemia vera)
Endothelial injury
Atherosclerosis
Elevated blood lipid and cholesterol levels
Smoking
Accelerated Activity of the Clotting System
Inherited disorders (primary)
Mutation in the factor V gene (factor V Leiden)
Mutation in the prothrombin gene
Acquired (secondary)
Prolonged bed rest or immobility
Oral contraceptive agents and pregnancy
Myocardial infarction
Heart failure
Malignant diseases
Antiphospholipid antibody syndrome
