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An Update on Hypercoagulable Disorders
Daniel G. Federman, MD;
Robert S. Kirsner, MD
Arch Intern Med. 2001;161:1051-1056.
ABSTRACT
Venous thrombosis is a cause of considerable morbidity and is often
responsible for chronic venous disorders that frequently lead to visits to
dermatologists and others involved in wound healing. Over the past several
years, many new causes of thrombophilia have been identified and have dramatically
altered the approach to patients presenting with thrombosis. Newly described
abnormalities associated with thrombophilia include the syndrome of activated
protein C resistance, the prothrombin 20210A mutation, hyperhomocysteinemia,
and elevated levels of coagulation factors VIII and XI. Clinicians can now
frequently determine causes of thromboses that have previously been deemed
idiopathic.
INTRODUCTION
Venous thrombosis is a cause of considerable morbidity and mortality.
It is also responsible for postphlebitic sequelae that lead to visits to primary
care physicians, dermatologists, vascular and plastic surgeons, and others.
In addition to the risk of embolization, as well as the acute symptoms of
pain and swelling, venous thrombosis can cause postphlebitic syndrome, which
consists of chronic leg pain, edema, induration, pigmentation, venectasia,
varicosis, and venous ulcers. This syndrome, which may occur in as many as
60% of patients with deep venous thrombosis (DVT),1
is thought to be caused by venous hypertension, damage to venous valves, and
abnormal microcirculation.2
Venous thrombosis is a common disorder. Approximately 1 in 1000 people
per year in the United States will develop clinically apparent venous thrombosis,
and there are 250 000 hospitalizations per year attributable to venous
thromboembolism (VTE). The incidence of fatal pulmonary embolism, for which
venous thrombosis is the major risk factor, is 50 000 people per year.3
Almost 150 years ago, the German pathologist Virchow4
postulated that thrombosis was due to stasis of the blood, changes in the
vessel wall, and changes in the composition of blood. Certain risk factors
for VTE have been known for some time, including surgery, trauma, malignant
neoplasms, immobility sepsis, congestive heart failure, nephrotic syndrome,
obesity, varicose veins, postphlebitic syndrome, oral contraceptives, and
estrogens. However, Virchow's "changes in composition of the blood," or thrombophilia
(also known as hypercoagulability), was not described until 1965, when Egeberg5 described inherited anti–thrombin III deficiency.
In the 1980s, deficiencies of the anticoagulant proteins, protein C and protein
S, were also found to be causes of inherited thrombophilia.6-7
However, these inherited deficiencies accounted for only 5% to 15% of VTE8 (Table 1).
Subsequently, the antiphospholipid antibody syndrome has been associated with
not only venous thrombosis but also arterial thrombosis.10
Over the past few years, considerable progress has been made in describing
inherited and other causes of this disorder. In this review, we will discuss
recent advances in diagnosing these newly described inherited and acquired
disorders.
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Deficiencies of Antithrombin III and Proteins C and S*
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ACTIVATED PROTEIN C RESISTANCE (FACTOR V LEIDEN)
In normal situations, a homeostasis exists between coagulation and fibrinolysis.
When coagulation is initiated, the process is regulated by a variety of mechanisms,
one of which is the protein C natural anticoagulant system. Thrombin, when
bound to thrombomodulin on the endothelial surface, activates protein C into
activated protein C (APC). Then APC inactivates activated factors V and VIII.
This is one of the mechanisms that inhibits thrombin generation and prevents
thrombosis from progressing unchecked.
In 1993, Dahlback et al11 described a
patient with a strong family and personal history of thrombosis who did not
possess any of the known hereditary coagulation defects. He found that when
APC was added to the patient's plasma, the activated partial thromboplastin
time (aPTT) did not prolong as expected. This phenomenon was termed APC resistance (APCR).
Subsequently, it was found that the defect in APCR does not lie in activated
protein C but is actually due to an abnormality in the APC cleavage site on
factor V. Approximately 90% to 95% of APCR is due to a single arginine to
glutamine mutation at position 506 of factor V, rendering it resistant to
degradation by APC.12 This mutation is known
as factor V Leiden, named after the city in which it was described. Since
this mutation accounts for 90% to 95% of APCR, a small percentage of patients
will harbor APCR in the absence of a factor V Leiden mutation.
One of the most common hereditary causes of thrombophilia, APCR has
been found in as many as 50% of selected patients13
and approximately 20% of unselected patients with thrombosis.14
Among European whites, the allele frequency in the general population is 4%,
but among native populations of Africa, Southeast Asia, and Australia, it
is extremely uncommon, if present at all.15
Among European whites, the frequency of factor V Leiden carriers has been
found to be even higher in certain populations. Among the general population,
it has been found in 13% in Cyprus,15 11% in
Sweden,16 and 9% in Turkey.17
The relative risk of thrombosis for carriers of the factor V Leiden mutation
is thought to be increased 7-fold for heterozygotes and 80-fold for homozygotes
in patients younger than 70 years without malignant neoplasms.18
This is an important cause of thrombosis even in elderly patients.19
Since lower extremity venous ulcers have been associated with previous
episodes of venous thrombosis, investigators have been interested in whether
there is an association between venous ulcers and APCR.20-21
In a study of 46 consecutive patients with chronic venous leg ulcers with
a mean age of 80 years and a median ulcer duration of 4 years, 12 (26%) were
found to be associated with APCR. These same investigators found APCR in only
1 (4%) of 23 healthy controls.22
There are several ways to test for this abnormality. The original aPTT-based
test, in which the aPTT is determined both with and without the addition of
APC, has been modified so that it can be performed when patients are receiving
anticoagulants. The APC is added to patient's plasma diluted 1:4 in factor
V–deficient plasma. An APC ratio is obtained by dividing the aPTT after
the addition of APC by the aPTT before the addition of APC; a ratio of less
than 2.0 is abnormal. The presence of a lupus anticoagulant may give rise
to an abnormal result.23 A polymerase chain
reaction–based test to test for the factor V Leiden mutation can either
be done initially, although it would not diagnose non–factor V Leiden
causes of APCR, or can be done after the APCR aPTT-based test.
THE PROTHROMBIN 20210A MUTATION
Human prothrombin is a single-chain, vitamin K–dependent protein
that is converted by the prothrombinase complex to thrombin during coagulation.
In 1996, Poort et al24 determined that of 28
selected patients with a family history of thrombosis, 5 (18%) possessed a
G to A nucleoside transition at position 20210 in the 3'-untranslated
region of the prothrombin gene. Of 100 healthy controls, only 1 was found
to harbor this mutation. Among patients with a first DVT in the Leiden Thrombophilia
Study, 6.2% were found to be heterozygous for this mutation, whereas only
2.2% of healthy controls possessed this mutation. In this study, the presence
of this mutation was associated with a relative risk of thrombosis of 2.8.24 Interestingly, heterozygous carriers were found to
have approximately 30% higher prothrombin levels than healthy controls, and
presumably, this is the mechanism by which it exerts its thrombotic effects.25
Other studies26-29
have suggested that the prevalence of this mutation among healthy controls
varies from 0.7% to 4.0%. Using data from 11 centers, Rosendaal et al30 found the prevalence to be 2.0%, which was slightly
higher in southern Europe (3.0%) than in northern Europe (1.7%). Similar to
factor V Leiden, this mutation is extremely uncommon in nonwhite populations.
Several other studies have looked at the prevalence of this mutation
among patients presenting with an episode of venous thrombosis and among the
healthy general population. The mutation was found in 4% to 8% of patients
with a first episode of thrombosis, representing a relative risk of first
venous thrombosis of 2 to 7 compared with the general population.31
The prothrombin 20210A mutation was found to be a risk for thrombosis
independent of factor V Leiden. Margaglione et al32
studied 281 patents with a first DVT referred to a center for thrombosis in
Italy. The 128 men with a mean age of 38 years and 153 women with a mean age
of 35 years were compared with a healthy matched cohort of 850 individuals.
In the group with DVT, 14.2% harbored the prothrombin 20210A mutation, whereas
the mutation was present in only 4.6% of controls. Factor V Leiden was present
in 18.5% of the DVT group and 5.1% of the controls. The adjusted odds ratio
for DVT was slightly higher for factor V Leiden (3.4) than prothrombin 20210A
(3.1). In this study, 14 patients were found to have both the factor V Leiden
and prothrombin 20210A mutations. The average age of their first thrombosis
was 31.5 years, which was younger than the 38 years for those with only the
prothrombin 20210A mutation and the 39 years for those with only factor V
Leiden. This suggests that patients who harbor both abnormalities are at increased
risk compared with those with a single abnormality of either factor V Leiden
or the prothrombin gene.
Although the prothrombin gene mutation is associated with elevated prothrombin
levels, it is not clear that assessing prothrombin levels is an adequate method
to test for this mutation. Currently, the recommended test for this mutation
is through DNA analysis.
RISK FOR RECURRENT EVENTS IN PATIENTS WITH FACTOR V LEIDEN OR THE PROTHROMBIN
GENE MUTATION
Whether the prothrombin gene mutation or factor V Leiden confers risk
for recurrent DVT after an initial thrombosis has been an area of investigation.
Unfortunately, there are conflicting data. Studies by Ridker et al33 and Simioni et al34
have found that patients who tested positive for factor V Leiden are at increased
risk for recurrent thrombosis when compared with patients who tested negative
for factor V Leiden. However, other studies35-36
have not been able to corroborate these findings.
The risk of recurrence is increased when patients harbor both the factor
V Leiden and prothrombin mutations. In a study of 624 patients with either
first or recurrent DVT who were referred to a thrombosis center, an evaluation
for inherited thrombophilia, including the prothrombin gene mutation, factor
V Leiden, antiphospholipid antibodies, malignant neoplasm, and deficiencies
of anti–thrombin III, protein C, or protein S, was performed. The investigators
found that 238 patients had no abnormalities and 129 were heterozygous for
factor V Leiden. Of these 129 patients who possessed the factor V Leiden,
17 also were heterozygous for the prothrombin gene mutation. At the time of
referral, the cumulative incidence of recurrent VTE was not statistically
different between those with the factor V Leiden mutation and those without.
However, among those with both mutations, the relative risk for recurrent
DVT was 2.6-fold increased compared with those with factor V Leiden alone.
When only spontaneous (those not occurring during times of increased risk
such as immobility, pregnancy, or surgery) recurrent DVTs were evaluated,
the relative risk was even higher.37
THERAPY
Patients with either factor V Leiden or the prothrombin 20210A mutation
who experience a first DVT should receive anticoagulation with warfarin sodium
for 3 to 6 months. Patients with recurrent thrombosis or those that harbor
both abnormalities and have had a first thrombosis should continue use of
warfarin indefinitely. At this time, it is not clear whether patients with
a first episode of thrombosis and a single abnormality will benefit from indefinite
anticoagulation. Trials looking to answer this question are being planned
or are currently under way.38
Although some practitioners might prescribe indefinite anticoagulation
for those with a single abnormality that experienced a life-threatening thrombosis
or thrombosis in an unusual site (cerebral, mesenteric), at present there
is no evidence to support or refute this practice.
RISKS ASSOCIATED WITH PREGNANCY AND THE USE OF ORAL CONTRACEPTIVES
It has long been known that the risk of thromboembolism is increased
during pregnancy and the puerperium. To evaluate whether the presence of factor
V Leiden or the prothrombin mutation increased the risk for thrombosis during
this period, investigators in Germany evaluated 119 women with a history of
thrombosis during pregnancy or the puerperium and 233 age-matched women. They
found factor V Leiden in 44% of patients with a history of thrombosis compared
with 8% of healthy women (relative risk, 9.3) and found the prothrombin gene
mutation in 17% of those with thrombosis compared with 1% of controls (relative
risk, 15.2). Based on their assumption that thrombosis occurs in 1 of 1500
pregnancies, the risk of thrombosis was estimated to be 0.2% among carriers
of factor V Leiden, 0.5% among those with the prothrombin mutation, and 4.6%
among those with both abnormalities.39
Female patients should be counseled that their risk of thrombosis is
increased not only during pregnancy and the puerperium but also if they choose
to use oral contraceptives. Studies have shown that patients with the prothrombin
gene mutation40 and the factor V Leiden mutation41-42 who use oral contraceptives are at
increased risk for venous thrombosis. Because of its teratogenic potential,
warfarin is contraindicated in women who are or may become pregnant.
ASSOCIATION BETWEEN THE FACTOR V LEIDEN AND PROTHROMBIN GENE MUTATIONS
AND ARTERIAL THROMBOSIS
Several studies43-45
have failed to show an association between either the factor V Leiden or the
prothrombin gene mutation and arterial disease, such as stroke or myocardial
infarction. However, there is a suggestion that these defects may contribute
to myocardial infarction in young women46-47
or in those with other risk factors for atherosclerosis.48
At this time, these 2 mutations are not thought to be a major cause of arterial
thrombosis.
HYPERHOMOCYSTEINEMIA
Homocysteine is a sulfur-containing amino acid formed during the metabolism
of methionine. Levels of homocysteine can be elevated through a variety of
genetic and environmental mechanisms, such as hereditary enzyme deficiencies
(such as cystathionine ß-synthase deficiency and methylene-tetrahydrofolate
reductase deficiency), chronic renal failure, hypothyroidism, certain malignant
neoplasms, or the use of methotrexate, phenytoin, or theophylline. However,
deficiencies of folate or vitamins B12 and B6 account
for two thirds of cases of hyperhomocysteinemia.49
There is strong evidence linking elevated homocysteine levels and arterial
disease. The Physicians' Health Study50 followed
up more than 14 000 physicians without known coronary artery disease.
Those with plasma homocysteine levels 12% above normal had a 3-fold increased
risk for the development of coronary artery disease than those with lower
levels. Furthermore, other studies51-56
have also shown an increased risk of myocardial infarction, stroke, and death
in patients with elevated homocysteine levels.
In addition to being a risk factor for arterial disease, hyperhomocysteinemia
has been shown to be a risk for venous thrombosis. Of 269 patients younger
than 70 years with a first episode of DVT participating in the Leiden Thrombophilia
Study, homocysteine levels above the 95th percentile were found in 10%, which
corresponds to an odds ratio of 2.5 when compared with a healthy matched control
group.57 This increased risk was independent
of other known risk factors for venous thrombosis, such as protein C, protein
S, antithrombin deficiencies, and APCR. Similarly, in a meta-analysis of 10
case-control studies, den Heijer et al58 found
an odds ratio of 2.5 for fasting homocysteine levels above the 95th percentile.
Furthermore, elevated homocysteine levels have also been shown to be associated
with a higher rate of recurrent thrombosis.59-60
The diagnosis of hyperhomocysteinemia can be made by measuring fasting
homocysteine plasma levels. Whereas the normal level is less than 15 µmol/L,
patients with mild disease have levels in the 15- to 30-µmol/L range,
patients with moderate disease have levels in the 30- to 100-µmol/L
range, and those with severe disease have higher levels. Methionine loading
stresses the homocysteine metabolic pathways and is thought to be more sensitive
than fasting levels in detecting homocysteine metabolic abnormalities.61 Homocysteine is measured before and 4 to 8 hours
after 100 mg/kg of oral methionine is given to a fasting patient. Hyperhomocysteinemia
is diagnosed if the plasma homocysteine level is more than 2 SDs above the
mean after the methionine load.49
Similar to patients with venous thrombosis who harbor no mutations or
either of the factor V Leiden or prothrombin 20210A mutations, those with
hyperhomocysteinemia and a first episode of thrombosis should be treated with
anticoagulation for 3 to 6 months. However, if a patient is deficient in folate
or vitamins B6 or B12, those vitamins should be administered
in sufficient doses to achieve normal levels. In the absence of a specific
vitamin deficiency, plasma homocysteine levels can be reduced up to 50% using
folic acid alone.62-63 Typically,
folic acid is given orally in doses of 1 to 2 mg/d. It is uncertain whether
the addition of vitamins B6 (pyridoxine hydrochloride)or B12 (cyanocobalamin) is of additional benefit to folic acid in the absence
of a specific vitamin deficiency. Although homocysteine levels have been shown
to decrease with folic acid supplementation, to date, we do not know whether
this will ultimately lead to a decreased frequency of adverse outcomes, such
as arterial or venous thromboses. Such studies are presently under way, and
their results are anxiously awaited.
ELEVATED FACTOR VIII LEVELS
Elevated levels of another protein involved in coagulation, factor VIII,
have also been associated with thrombosis. In multivariate analysis, Koster
et al64 found that when compared with subjects
with factor VIII levels of 1000 IU/L or less, those with levels greater than
1500 IU/L possessed an almost 5-fold increased risk for thrombosis. Of patients
with a first episode of DVT, 25% were found to have levels above 1500 IU/L
compared with 11% of healthy matched controls. In addition, in patients with
unexplained thromboembolism referred for thrombophilia screening, elevated
factor VIII levels were the most common abnormality detected.65
Some have suggested that a C-reactive protein level should be measured to
exclude elevated factor VIII levels as an acute-phase reactant, since levels
can increase during acute illness.66 At this
time, little is known as to how elevated factor VIII levels affect the treatment
of VTE.
ELEVATED FACTOR XI LEVELS
Increased levels of a component of the intrinsic factor pathway, factor
XI, have recently been implicated as a risk factor for venous thrombosis.67 Investigators measured the factor XI antigen levels
of patients enrolled in the Leiden Thrombophilia Study and found that the
relative risk of thrombosis for patients with levels above the 90th percentile
was 2.2 compared with those with levels at or below that value. A continuous
dose-response relation was noted; the higher the factor XI level, the higher
the risk of thrombosis. Furthermore, this increased risk was independent of
other known risk factors for thrombosis, such as oral contraceptive use, older
age, and elevated levels of factor VIII and homocysteine. When patients with
known genetic causes of thrombophilia, such as the prothrombin 20210A or factor
V Leiden mutations, or deficiencies of antithrombin or proteins C or S were
excluded from analysis, the odds ratio did not change. This suggests that
the increased risk seen in patients with elevated factor XI levels is not
due to an association with these known causes of thrombophilia. The authors
determined that in the general population up to 11% of all cases of thrombosis
might be attributable to high levels of factor XI. Studies are under way to
determine whether increased levels of this factor are genetically determined.67
WHOM TO EVALUATE
Since these risks for thrombosis are recently described, there are no
large, well-done studies to assess an optimal, cost-effective approach with
regard to screening and case finding for these disorders. It would be reasonable
to pursue a workup for those with any of the following: thrombosis at an early
age (younger than 45 to 50 years), a family history of thrombosis, or recurrent
thrombosis. Some clinicians might also order these tests if the patient developed
a thrombosis at an unusual site (eg, mesenteric, cerebral, or hepatic vein
thromboses) or for a patient who presented with a life-threatening event.
For patients who develop thrombosis before the age of 45 to 50 years
and in those with a family history of thrombosis, it would be reasonable to
order tests to evaluate whether the patient has 1 of the following disorders:
deficiencies of anti–thrombin III, protein C, and protein S or the presence
of antiphospholipid antibody syndrome, factor V Leiden, prothrombin 20210A
mutation, and hyperhomocysteinemia. For those who develop their first episode
of thrombosis after the age of 45 to 50 years and without a family history
of thrombosis, it would be reasonable to omit tests looking for deficiencies
of anti–thrombin III, protein C, or protein S, since these disorders
would be much less likely.
Clinicians should be aware that levels of protein C, protein S, and
antithrombin III are decreased in acute thrombosis, and therefore they should
not check these levels during an acute event. Furthermore, antithrombin III
levels are decreased by the administration of heparin sodium, and therefore
should not be measured when the patient is receiving this anticoagulant. Since
proteins C and S are vitamin K dependent, their levels are reduced during
therapy with warfarin sodium; levels should be measured after the patient
has been free of warfarin for at least 2 weeks. Currently, the role of screening
for elevated factor VIII and XI levels is not clear.
CONCLUSIONS
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