[Modifiable and Non-Modifiable]{#OLE_LINK1} Risk Factors for Venous
Thrombosis

[Prepared for the Surgeon General's Workshop of Deep Vein
Thrombosis]{.underline}

[May 8-9, 2006]{.underline}

[Bethesda, MD]{.underline}

[Mary Cushman, MD, MSc]{.underline}

[Associate Professor of Medicine and Pathology]{.underline}

[Director, Thrombosis and Hemostasis Program]{.underline}

[University of Vermont College of Medicine and Fletcher Allen Health
Care]{.underline}

[Burlington, Vermont]{.underline}

[Correspondence:]{.underline}

[Mary Cushman, MD, MSc, Department of Medicine, University of Vermont,
208 South Park Drive, Suite 2, Colchester, VT 05446. phone:
802-656-8968; fax: 802-656-8965; email: ]{.underline}

[Introduction]{.underline}

[Deep vein thrombosis, or DVT, is the occurrence of an abnormal blood
clot within a vein (venous thrombosis), usually occurring in the leg
veins. The danger of DVT is that pieces of the clot can break free and
travel to the lung. This is known as pulmonary embolus, or PE, and it
happens about one-fourth of the time a DVT occurs. DVT and PE usually
happen suddenly, with typical symptoms of leg pain or swelling (in the
case of DVT), or shortness of breath or chest pain (in the case of PE).
Early recognition of symptoms is necessary to allow early diagnosis and
life-saving treatment. PE is a life-threatening problem because patients
with PE cannot add oxygen to the blood normally in the lungs. The major
risk factors for DVT and PE are listed here:]{.underline}

-   [Older Age]{.underline}

-   [Obesity / Overweight]{.underline}

-   [Personal History of Prior Venous Thrombosis]{.underline}

-   [Family Member with Venous Thrombosis]{.underline}

-   [Surgery]{.underline}

-   [Hospitalization for Surgery or Medical Condition]{.underline}

-   [Cancer]{.underline}

-   [Trauma / Injury, especially of the legs]{.underline}

-   [Immobility (longer than 4 days)]{.underline}

-   [Varicose Veins]{.underline}

-   [Pregnancy]{.underline}

-   [Contraceptive Medications]{.underline}

-   [Postmenopausal Hormone Medications, including estrogen
    modulators]{.underline}

-   [Long Air Travel]{.underline}

-   [Genetic (inherited) Factors Affecting Clotting Balance]{.underline}

[These risk factors include a combination of personal factors, like
obesity, and episodic situations (triggers) that enhance risk, like
surgery or pregnancy. Some of the risk factors are modifiable and
others, like advancing age, are not. When more than one risk factor is
present, the risks add together.]{.underline}

[It is important to understand the risk factors for DVT and PE so that
patients can be aware of particular settings that enhance their own
risk. Sometimes patients develop typical symptoms following high risk
settings such as surgery, but evaluation by a physician is delayed due
to low awareness by the patient. This delay in diagnosis can lead to
worse outcomes of treatment. ]{.underline}

[Modifiable Risk Factors]{.underline}

*[Obesity]{.underline}*

[An important modifiable risk factor for thrombosis is obesity. Obesity
is defined as a body-mass index (BMI) above 30
kg/M]{.underline}^[2]{.underline}^[. BMI can be calculated as weight in
kilograms (kg) divided by height in meters squared, and there are
internet sites for assistance in the calculation (). It is important for
every person to know their BMI, since one does not need to look 'fat' to
be classified as obese, based on the current standard definition.
Obesity leads to a 2 or 3-fold higher chance of having a thrombosis
episode . The risk of thrombosis associated with severe obesity (BMI
above 40 kg/ M]{.underline}^[2]{.underline}^[) is even higher. Obese
persons have a further increase in thrombosis risk when they are exposed
to other thrombosis risk factors, such as contraceptives or
postmenopausal hormones . ]{.underline}

[The association of obesity with thrombosis is especially important
currently in the United States because obesity is increasing
dramatically. Between 1991 and 2004 rates of obesity have more than
doubled, with estimates as high as 30% in some areas of the United
States. To illustrate the impact of this obesity epidemic on expected
rates of thrombosis in the United States we used data from the United
States Census and the Centers for Disease Control and Prevention to
estimate the rates of thrombosis attributed to obesity from 1990 to
2000. We estimate that in 1990 there were 18,500 cases of venous
thrombosis among obese people aged 45-64 years (based on the number of
people in that age range, a prevalence of obesity of 10% at that time,
and the expected rate of thrombosis with obesity compared to normal
weight). However, in 2000, we estimate that with a 25% rate of obesity,
there were 62,000 cases of thrombosis among obese persons aged 45-64. If
the prevalence of obesity had stayed at 10% in 2000, only 24,000 cases
of thrombosis would have been expected in obese persons in 2000. Thus,
in 2000, there were 38,000 excess thrombosis cases among people aged
45-64 solely due to the rise in obesity.]{.underline}

*[Other Risk Setttings]{.underline}*

[These conditions increase the risk of thrombosis, usually for a number
of weeks following exposure. As described above, when there is more than
one of these conditions present at the same time (along with the other
risk factors above), the risk is higher. For example, if a patient were
hospitalized for treatment of pneumonia and also had recent trauma to
the leg, the risk of thrombosis would be higher in general than a
patient without recent trauma .]{.underline}

[ ]{.underline}*[Hospitalization]{.underline}*

[Most hospitalized patients have risk factors for venous thrombosis.
These commonly include immobility, cancer, infection and surgery. Up to
20% of patients admitted to a medical service will have thrombosis and
up to 40% admitted to a surgical service. Many of these events are not
clinically apparent, but still could lead to later problems like
pulmonary embolus. About 10% of all deaths in the hospital are related
to pulmonary embolus, and many times it was not suspected before death .
For this reason it is important that most patients admitted to a
hospital receive preventive treatments against venous thrombosis
.]{.underline}

[ ]{.underline}*[Surgery]{.underline}[/Trauma]{.underline}*

[The risk of thrombosis with surgery varies depending on the surgery
type and patient characteristics like age and obesity. In general,
preventive treatments are used to reduce the chance of developing venous
thrombosis after surgery. These treatments vary from something as simple
as getting out of bed quickly after surgery to use of anticoagulant
medications and mechanical devices placed on the legs. The
aggressiveness of the preventive treatments used depends on the known
risk of the particular surgery and on patient characteristics such as
the risk profile for thrombosis and the risk of bleeding with surgery.
The highest risk surgical patients tend to be those with hip or knee
replacement, spinal cord injury, or multiple trauma. Detailed discussion
is beyond the scope of this chapter but the periodically published
guideline statement of the American College of Chest Physicians is a
useful resource for more detail . ]{.underline}

[ ]{.underline}*[Immobility]{.underline}*

[Persons who are immobilized are at high risk of thrombosis. The reason
is likely related to slowing of blood flow in the veins. Examples of
states of immobility include use of a plaster cast on the leg or
bedrest. Lesser degrees of immobility such as placement of leg splints
may also play a role, but it is smaller.]{.underline}

[ ]{.underline}*[Cancer]{.underline}*

[Cancer patients have an increased risk of thrombosis due to a
combination of factors. Tumor cells release substances that activate the
clotting system, tumors themselves can block blood flow in veins and
cancer patients are exposed to treatments such as surgery and
chemotherapy, with attendant hospitalizations that increase their risk.
It is particularly important that cancer patients receive good
preventive treatments during other high risk settings, like surgery or
hospitalization.]{.underline}

*[Travel]{.underline}*

[Any sort of travel has potential to increase the risk of thrombosis. It
appears that duration of travel is a key factor. Thus, travel by air,
car, train or bus for 4 or more hours all increase the risk by about
2-fold for several weeks after travel . As before, the risk is higher
when other thrombosis risk factors are present.]{.underline}

[Non-Modifiable Risk Factors]{.underline}

*[Age]{.underline}*

[The risk of venous thrombosis rises substantially with age, especially
after age 40. Thus it is important to consider this underlying factor in
planning preventive strategies for those with other risk
factors.]{.underline}

*[Genetic Factors]{.underline}*

[Patients with venous thrombosis commonly have an underlying genetic
predisposition. Genetic risk factors enhance the risk of venous
thrombosis during risk periods ("triggered thrombosis), and of
thrombosis occurring in the absence of these triggers (termed idiopathic
thrombosis). About one-half of cases of venous thrombosis occur on an
idiopathic basis, which suggests that substantial reductions in the
incidence of thrombosis would occur if the triggered episodes could be
prevented.]{.underline}

[Over the past 20 years several hematologic disorders have been
identified as risk factors for venous thrombosis (see Table 1). These
conditions are often referred to as "thrombophilic disorders,"
"thrombophilias" or "hypercoagulable syndromes". Most of these
conditions have been defined in European (Caucasian) populations and are
less frequent in non-Caucasians. Many thrombophilias are genetic
disorders that are evaluated in the clinical laboratory by DNA analysis
or coagulation factor activity levels. There are other disorders being
investigated in research settings but table 1 lists those most commonly
used in clinical practice.]{.underline}

[Use of testing for genetic or acquired thrombophilic disorders has
become widespread on the basis of the associations of these disorders
with risk of a first venous thrombosis. However, the clinical utility of
this testing is not certain. Patient groups considered for this testing
include those who have had thrombosis and their family members, who have
not. To be clinically useful for a patient with thrombosis, it would be
desirable if the testing helped identify a particular treatment strategy
for prevention of recurrent thrombosis. Only a few studies are available
to date on thrombophilia disorders and prediction of recurrent events.
Whether these tests provide information that is useful for clinical
management in decision-making about use of long-term anticoagulation is
not yet clear . It is possible that some tests of overall clotting
activity, such as D-dimer tests might be more useful in guiding clinical
decision-making than tests for specific clotting disorders
.]{.underline}

[Considering testing for family members of those with thrombosis and an
identified thrombophilia, the role of genetic testing is even less
clear. It might be expected that the knowledge of a risk factor would
reduce the likelihood of future thrombosis in affected family members,
but this remains to be proven in scientific studies.]{.underline}

[Among patients undergoing thrombophilia testing after a thrombosis
episode, about 15%-20% will have factor V Leiden, 5% prothrombin 20210A,
20% elevated factor VIII and 5%-10% an anticoagulant protein deficiency
(protein C, protein S or antithrombin). Rates of positive tests are
higher among patients with a family history of thrombosis and will
differ in non-Caucasian ethnic groups.]{.underline}

[Interaction of Risk Factors in Thrombosis]{.underline}

[As discussed above, venous events often occur when multiple risk
factors, including genetic and environmental, are present at the same
time . A classic illustration of this point is the interaction of oral
contraceptive use and factor V Leiden. It is estimated that women
heterozygous for factor V Leiden have a 3- to 7-fold increased risk of
VT. Oral contraceptives confer a 2-3-fold increase in risk. In the
presence of both risk factors, the relative risk is 34-fold increased .
This is likely due to the fact that oral contraceptives induce activated
protein C resistance, making the biochemical defect associated with
factor V Leiden worse . ]{.underline}

[To further illustrate how venous thrombosis risk factors work together,
as a woman with factor V Leiden ages her thrombosis risk increases. If
she began postmenopausal estrogen plus progestin in her fifties, her
chance of developing a venous thrombosis would approach 1% for each year
of use (compared to the healthy baseline risk of 0.1%) . If this woman
were obese her chance would approach 1.5% each year . If this woman had
used contraceptives in her twenties, her yearly venous thrombosis risk
would have been only 0.3% (0.4% if she were obese) because of her young
age. Thus, before prescription, any woman considering hormone therapies
needs education on the risk of thrombosis (and its symptoms), but older
women who are obese deserve special attention due to their high
risk.]{.underline}

[Similarly, thrombosis risk is usually higher when there is more than
one inherited risk factor for thrombosis, such as factor V Leiden and
protein C deficiency together, where the relative risk of thrombosis is
higher than in the presence of a single disorder. ]{.underline}

[Because this is an active research area that is continually changing,
and the interrelations of genetics, personal characteristics, and
thrombosis triggers are complex, when testing for genetic conditions is
considered, it is best done by a physician experienced in thrombosis
genetics. ]{.underline}

[How Can we Intervene to Reduce Risk?]{.underline}

[There are several interventions that might be effective in reducing the
population risk of venous thrombosis. Methods relate to changing the
modifiable risk factors or providing preventive treatments during
situations of high risk. Considerations may be made in the following
categories:]{.underline}

*[Personal Level]{.underline}*

[Modification of lifestyle factors and active participation in one's
medical care are key factors in reducing the risk of venous thrombosis.
Treatment and prevention of obesity, for example could have an important
impact on the national rates of thrombosis. Awareness of one's own
personal risk profile and discussion of this with care providers can
help to ensure optimal use of preventive treatments during high risk
periods. For example, an individual with a previous thrombosis would be
at very high risk of thrombosis during a trigger setting such as
surgery. It is critical that this person make their surgeon aware of the
previous thrombosis episode.]{.underline}

*[Public Edu]{.underline}[cation to I]{.underline}[ncrease
]{.underline}[Awareness of the D]{.underline}[isease]{.underline}*

[Many are not aware of what venous thrombosis is, or the symptoms. Early
recognition can prompt early treatment and potentially reduce the
complications of thrombosis. Public awareness could enhance
understanding of the risk factors listed in this chapter as
well.]{.underline}

*[System Level]{.underline}[ Improvements]{.underline}*

[Institutions such as hospitals and nursing homes should have standard
procedures in place to prevent venous thrombosis. In hospital settings
this might involve interventions discussed elsewhere in this document,
such as electronic reminders for physicians to prescribe preventive
treatments.]{.underline}

*[Promote ]{.underline}[E]{.underline}[ducation of
]{.underline}[H]{.underline}[ealth ]{.underline}[C]{.underline}[are
]{.underline}[P]{.underline}[roviders on
]{.underline}[P]{.underline}[reventive]{.underline}[ Methods for
Thrombosis]{.underline}*

[There has been a wealth of new information in recent years on methods
for prevention of venous thrombosis. This information must be translated
efficiently to medical practice.]{.underline}

[Table 1. Common Genetic Conditions Associated with Risk of Venous
Thrombosis]{.underline}

  -------------------------------------------------------------------------
  [Factor V Leiden mutation / Activated protein C resistance]{.underline}
  [Prothrombin 20210A mutation]{.underline}
  [Protein C deficiency]{.underline}
  [Protein S Deficiency]{.underline}
  [Antithrombin deficiency]{.underline}
  [Elevated factor VIII\*]{.underline}
  -------------------------------------------------------------------------

**[\* ]{.underline}**[elevated factor VIII tends to be found in families
and is partly related to blood type. The precise genetic disorder
causing this is not known.]{.underline}

**[References]{.underline}**