cushman risk factors by HC120727193915


									             Modifiable and Non-Modifiable Risk Factors for Venous Thrombosis

Prepared for the Surgeon General’s Workshop of Deep Vein Thrombosis
May 8-9, 2006
Bethesda, MD

Mary Cushman, MD, MSc
Associate Professor of Medicine and Pathology
Director, Thrombosis and Hemostasis Program
University of Vermont College of Medicine and Fletcher Allen Health Care
Burlington, Vermont

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:

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
      Older Age
      Obesity / Overweight
      Personal History of Prior Venous Thrombosis
      Family Member with Venous Thrombosis
      Surgery
      Hospitalization for Surgery or Medical Condition
      Cancer
      Trauma / Injury, especially of the legs
      Immobility (longer than 4 days)
      Varicose Veins
      Pregnancy
      Contraceptive Medications
      Postmenopausal Hormone Medications, including estrogen modulators
      Long Air Travel
      Genetic (inherited) Factors Affecting Clotting Balance

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

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.

Modifiable Risk Factors
An important modifiable risk factor for thrombosis is obesity. Obesity is defined as a body-mass
index (BMI) above 30 kg/M2. 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 1-3. The risk of
thrombosis associated with severe obesity (BMI above 40 kg/ M2) 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 2,4.

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.

Other Risk Setttings
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 5.

       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 6. For this reason it is
       important that most patients admitted to a hospital receive preventive treatments against
       venous thrombosis 7.

       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 7.

       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.

       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.

       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 8. As before, the risk is
       higher when other thrombosis risk factors are present.

Non-Modifiable Risk Factors
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.

Genetic Factors
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.

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.

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 9-15. 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 15,16.

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.

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.

Interaction of Risk Factors in Thrombosis
As discussed above, venous events often occur when multiple risk factors, including genetic and
environmental, are present at the same time 17. 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 18. 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 19.

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%) 4. If this woman were obese her chance
would approach 1.5% each year 4. 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) 2,18 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.

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.

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.

How Can we Intervene to Reduce Risk?
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

Personal Level
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.

Public Education to Increase Awareness of the Disease
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.

System Level Improvements
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

Promote Education of Health Care Providers on Preventive Methods for Thrombosis
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.

Table 1. Common Genetic Conditions Associated with Risk of Venous Thrombosis
Factor V Leiden mutation / Activated protein C resistance
Prothrombin 20210A mutation
Protein C deficiency
Protein S Deficiency
Antithrombin deficiency                                   * elevated factor VIII tends to be
Elevated factor VIII*                                     found in families and is partly
                                                          related to blood type. The precise
genetic disorder causing this is not known.


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