CARDIOLOGY PATIENT PAGE
Deficiencies of Natural Anticoagulants, Protein C, Protein S,
and Antithrombin
Brea Lipe, MD; Deborah L. Ornstein, MD
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Y
ou or a family member may have
developed a blood clot in one of
the deep veins in the body (ie, a deep
vein thrombosis, or DVT) or had a
blood clot that traveled to the lungs (ie,
a pulmonary embolism, or PE). As part
of your medical care, your doctor may
have evaluated you for conditions that
may have contributed to developing a
blood clot.
Thrombophilia is a condition in
which there is an increased tendency to
form blood clots. It may be hereditary
and conferred by genes inherited from
one or more parents, or it may be
acquired through situations such as
surgery, cancer, pregnancy, or certain
medications (eg, some contraceptive
and menopausal hormone replacement
products). The two most common hereditary thrombophilia conditions are
the factor V Leiden and prothrombin
20210 gene mutations, both of which
have been the subject of previous Cardiology Patient Pages.1,2 This Cardiology Patient Page will describe deficiencies in the natural anticoagulants,
protein C, protein S, and antithrombin
that may result in either hereditary or
acquired thrombophilia.
What Are the
Natural Anticoagulants?
Blood flows through blood vessels to
deliver oxygen and nutrients to all the
body’s tissues. When a blood vessel is
injured, a process called coagulation
causes blood to form clots that stop the
bleeding from the damaged blood vessel. Once coagulation begins, other
substances in the blood, the natural
anticoagulants, act as brakes to limit
coagulation to the specific area of
damage, thus avoiding formation of
clots large enough to obstruct normal
blood flow. There is a delicate balance
at work to ensure that there is
enough— but not too much— clotting
ability in the blood. Too little clotting
ability leads to bleeding problems,
whereas too much clotting ability
(thrombophilia) can lead to blood clot
formation. The state of this balance
between bleeding and clotting differs
from person to person, and many
things can upset the balance (Figure).
Because the natural anticoagulants are
required to help stop the clotting process,
deficiencies of one of these substances
can upset this balance and lead to thrombophilia. The most important natural anticoagulants are protein C, protein S, and
antithrombin (which used to be called
antithrombin III until its name was
changed to antithrombin).
What Causes Deficiencies of
the Natural Anticoagulants?
Low levels of the natural anticoagulants or natural anticoagulants that do
not work properly can either be inherited or may occur during certain life
events. Genes, including those for the
natural anticoagulants, are inherited
from your parents in 2 copies, 1 from
your mother and 1 from your father.
People born with deficiencies of one of
the natural anticoagulants inherit one
abnormal gene from either their
mother or father. Rarely, people can
inherit abnormal genes from both parents, but this often results in severe
clotting problems that are diagnosed in
infancy. People who have inherited
normal levels of the natural anticoagulants may nevertheless develop deficiencies in certain situations, such as
pregnancy, liver disease, severe infection or other illness, vitamin K deficiency, and certain medications, eg,
estrogen, heparin, and warfarin. In addition, a recent blood clot may also
From Hematology/Oncology (B.L.) and Hemophilia and Thrombosis Center (D.L.O.), Dartmouth-Hitchcock Medical Center, Lebanon, NH;
Departments of Medicine and Pathology, Dartmouth Medical School, Hanover, NH (D.L.O.).
Correspondence to Deborah L. Ornstein, MD, Hemophilia & Thrombosis Center, Dartmouth-Hitchcock Medical Center, One Medical Center Drive,
Lebanon, NH 03756. E-mail [email protected]
(Circulation. 2011;124:e365-e368.)
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.111.044412
e365
e366
Circulation
October 4, 2011
Ancoagulants:
protein c
protein S
anthrombin
Procoagulants
Clong
Bleeding
A
Ancoagulants:
protein c
protein S
anthrombin
Procoagulants
Clong
Bleeding
B
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Figure. The normal balance between clotting and bleeding is disrupted when there is a
deficiency of one of the natural anticoagulants. There is a fine balance between clotting
and bleeding in the blood. The substances that cause normal blood clots to form
(called procoagulants) are carefully balanced by the natural anticoagulants (A) so that
enough clotting occurs to prevent bleeding, but not so much as to trigger a large blood
clot that obstructs a vein and prevents blood from flowing. When there is a deficiency in
one of the natural anticoagulants (B, downward arrow), the balance is tipped in the
direction of clotting such that individuals with these deficiencies have an increased propensity to form abnormal blood clots.
reduce blood levels of the natural
anticoagulants.
How Is the Diagnosis Made?
Testing is accomplished with a blood
test to measure the levels and activity
of the natural anticoagulants in your
blood. Testing should be done at
least several weeks after an acute
clotting episode and at least 3 to 6
weeks after stopping warfarin or heparin. Repeat testing should be done
to confirm abnormal results, because
false-positive results are common.
For example, birth control pills and
pregnancy often cause a falsely low
level of protein S.
What Are the Implications?
Inherited deficiencies of the natural
coagulants are uncommon. Protein C
deficiency occurs in ⬇1 of every 200
to 500 people, whereas protein S deficiency can be expected in ⬇1 of every
500 individuals. Antithrombin deficiency is the least common of the 3
deficiencies, occurring in ⬇1 of every
2000 to 5000 people.
People with hereditary protein C or
protein S deficiency have about a 2- to
11-fold increased risk for developing a
DVT or PE in comparison with those
without a deficiency. This translates
roughly to a DVT or PE occurring in
⬇1 of every 100 to 500 people with
one of these deficiencies annually.
Antithrombin deficiency is associated with a higher risk for developing
a DVT and PE, and it is estimated
that up to 50% of people with hereditary antithrombin deficiency will
experience a blood clot in their
lifetimes.
Deficiencies of the natural anticoagulants are associated primarily with an
increased risk for blood clots in veins,
and seem to play little or no role in
development of blood clots in arteries,
eg, heart attack and stroke. However, a
recent study suggests that protein C
and protein S (but not antithrombin)
deficiencies may be associated with an
increased risk for forming arterial
blood clots in people younger than 55
years.
Although associated with an increased risk for forming blood clots, it
is important to remember that many
(perhaps most) people with deficiencies of the natural anticoagulants will
never experience complications from
the deficiency.
How Are Deficiencies
of the Natural
Anticoagulants Treated?
If you have had a DVT or PE, you
were most likely treated with anticoagulants (blood thinners). Warfarin is
currently the most commonly prescribed anticoagulant for long-term
treatment after a DVT or PE, but it
must be given initially with an additional injectable anticoagulant (usually
heparin, low-molecular-weight heparin, or a similar drug) until the warfarin
is fully effective. If you have protein
C or protein S deficiency, you must
never receive warfarin without first
receiving another anticoagulant at
the same time. Warfarin inhibits the
body’s own production of protein C
and protein S. Therefore, initial treatment with warfarin alone in people
with protein C or protein S deficiency may temporarily make clotting worse or precipitate a new clot
or a severe skin rash known as skin
necrosis. It is usually safe to take
warfarin alone after 5 or more days
of concurrent treatment with heparin,
low-molecular-weight heparin, or a
related drug, such as fondaparinux.
After a first DVT or PE, the risk for
developing a second clot is probably
higher for individuals with a deficiency of one of the natural anticoagulants than for those without this deficiency. Although lifelong treatment
with an anticoagulant is not always
recommended after a first blood clot,
the duration of anticoagulant treatment
will depend on the exact type of natural anticoagulant deficiency you have,
the circumstances of your clot, and
other risk factors you may have.
Therefore, anticoagulation duration
will need to be carefully considered
with your physician.
If you have a deficiency of one of
the natural anticoagulants but have
never had a blood clot, then you will
not routinely be treated with an anticoagulant. However, you should focus
on reducing or eliminating other factors that may add to your risk of
developing a blood clot in the future
(Table 1). In addition, you may require
temporary treatment with an anticoagulant during periods of particularly
high risk, such as surgery or pregnancy. It is very important, therefore,
that you let all your doctors know if
you have such a deficiency.
Lipe and Ornstein
Table 1.
Risk Factors for DVT and PE
Obesity
Deficiencies of Natural Anticoagulants
Table 2. Steps to Take to Minimize the
Risk for Developing a DVT or PE
Immobilization
Maintain an ideal body weight
Surgery
Engage in regular physical activity
Hospitalization for medical illness
Do not smoke
Trauma
Avoid long periods of immobility (⬎2 h)
Prolonged travel
Cigarette smoking
Advancing age (risk doubles for every decade
of life)
Pregnancy
Chronic illnesses
Congestive heart failure (CHF)
Get up to walk around or stretch during
airplane flights or long car trips
Consider the use of elastic compression
stockings that provide moderate compression
(15–20 mm Hg)
Drink water to maintain hydration
Avoid alcohol and caffeine during travel
If you are planning to have surgery
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Chronic obstructive pulmonary disease
(COPD)
Alert your doctor to any genetic risk factors
Cancer
Work with your doctors to identify strategies
to reduce your risk
Inflammatory bowel diseases (eg, Crohn’s
disease, ulcerative colitis)
Recognize the symptoms of a DVT or PE and
seek medical attention should they occur
Systemic lupus erythematosus and other
rheumatologic disorders
Shortness of breath and/or chest pain
Myeloproliferative disorders
Unexplained pain, swelling, and/or redness of
a limb
Hormone therapy
Contraceptives
Menopausal hormone replacement therapy
(HRT)
Other inherited or acquired alterations in the
blood clotting system
DVT indicates deep vein thrombosis; PE, pulmonary embolism.
What Are Special
Considerations for Women
With a Deficiency of One of
the Natural Anticoagulants?
Deficiencies of the natural anticoagulants demand special consideration
during times of pregnancy or hormone
use (oral contraceptives or menopausal
hormone replacement therapy). Hormone use is associated with an increased risk for blood clots in the
general population, but the risk is even
higher for women with natural anticoagulant deficiencies. Although medications that contain estrogen appear to
be associated with the highest risk,
progestin-only contraceptives may
also increase the risk somewhat. It is
important to note that progestin-only
contraceptives have a higher failure
rate and thus a higher rate of pregnancy than combined oral contracep-
DVT indicates deep vein thrombosis; PE, pulmonary embolism.
tives containing both estrogen and progestin. In addition, progestin-only
contraceptives have an increased risk
of irregular bleeding that may lead
some women to discontinue the medication. The levonorgestrel-secreting
intrauterine device (Mirena) is not associated with an increased risk for
developing blood clots and is often
recommended for women with thrombophilia or a history of blood clots.
Although the levonorgestrel intrauterine device also has a risk of irregular
bleeding, the first-year failure rate carries a much lower risk of pregnancy
than other contraceptive methods.
Women should review the risks and
benefits of the various options with
their doctors before deciding on hormone use.
During pregnancy and for the first 4
to 6 weeks after delivery, there is an
increased risk for developing blood
clots in all women. This rate is higher
for those with than for those without a
deficiency of one of the natural anticoagulants. There may also be an increased risk for early and late term
miscarriages. Women with a defi-
e367
ciency of one of the natural anticoagulants who are planning a pregnancy
should work closely with their obstetrician, hematologist, and/or thrombosis expert consultant to determine the
appropriate treatment during and after
pregnancy.
Who Should Be Tested for
Deficiencies of the
Natural Anticoagulants?
You may consider testing if you develop a blood clot and have a family
member with a deficiency of one of the
natural anticoagulants or if you have
unexplained or recurrent DVTs or PEs
without a family history. Other situations may arise in which testing can be
considered after discussion with your
physician. Testing healthy relatives of
people with a natural anticoagulant
deficiency is controversial and should
be discussed carefully with your physician. Advantages of testing may include increased awareness of the risk
factors for and symptoms of blood
clots. Disadvantages include possible
anxiety regarding a diagnosis that may
never produce symptoms, lack of insurance coverage for inappropriate
testing, and unnecessary withholding
of certain medications, like oral contraceptives or hormone replacement
therapy.
How Do I Minimize the Risk
Caused by Deficiencies of the
Natural Anticoagulants?
Although the genetic risk from natural
anticoagulant deficiencies cannot be
altered, individuals can make lifestyle
modifications to reduce additional risk
factors. A major risk factor for blood
clots is obesity, for example, which
poses a more potent risk than some of
the hereditary thrombophilias. Tips for
reducing risk for DVT and PE are
listed in Table 2.
Conclusions
Natural anticoagulant deficiencies
are rare and are either inherited at
birth or acquired sometime during
life. Natural anticoagulant deficiencies are one of many conditions that
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Circulation
October 4, 2011
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can increase the risk for developing a
DVT or PE (Table 1), but many
people with such a deficiency will
never develop blood clots. Although
the inherited risks cannot be altered,
many things can be done to decrease
an individual’s overall risk of developing blood clots (Table 2). A heart
healthy lifestyle is of paramount importance to minimizing thrombosis
risk. Recognizing the symptoms of a
DVT or PE allows for prompt treatment to minimize the risk of lasting
side effects. Finally, it is important to
work with your doctor to understand
your individual risk, preventive strategies, and therapeutic options in the
event of a DVT or PE.
Additional Resources
1. Heit J. Thrombophilia: common
questions on laboratory assessment and management. Hematology Am Soc Hematol Educ Program. 2007:127–135.
2. Foy P, Moll S. Thrombophilia:
2009 update. Curr Treat Options Cardiovasc Med. 2009;11:
114 –128.
3. Middeldorp S, van Hylckama
Vlieg A. Does thrombophilia
testing help in the clinical management of patients? Br J Hematol. 2008;143:321–335.
4. Dalen JE. Should patients with
venous thromboembolism be
screened for thrombophilia? Am J
Med. 2008;121:458 – 463.
5. National Blood Clot Alliance.
Website of the nonprofit patient
organization, NBCA. Available
at: http://stoptheclot.org.
6. North American Thrombosis Forum. Website of the nonprofit
organization, NATF. Available
at: www.NATFonline.org.
Disclosures
None.
References
1. Ornstein DL, Cushman M. Factor V Leiden.
Circulation. 2003;107:e94 – e97.
2. Varga EA, Moll S. Prothrombin 20210
mutation (factor II mutation). Circulation.
2004;110:e15– e18.
Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin
Brea Lipe and Deborah L. Ornstein
Circulation. 2011;124:e365-e368
doi: 10.1161/CIRCULATIONAHA.111.044412
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
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