Deep Vein Thrombosis and Pulmonary Embolism (DVT/PE) represent a major public health problem, exacting a significant human and economic toll on the Nation. These common conditions affect hundreds of thousands of Americans each year. A 25-year population-based study published in 1998 found that the overall age- and sex-adjusted annual incidence of VTE was 1.17 per 1,000 (.48 per 1,000 for DVT and .69 per 1,000 for PE) 8. Applying these figures to today’s population of approximately 300 million Americans suggests that more than 350,000 individuals are affected by DVT/PE each year 9. A 1991 study that extrapolated findings from 16 short-stay hospitals in Worcester, Massachusetts is fairly consistent with these estimates. This study found that approximately 270,000 individuals were hospitalized for DVT/PE in 1991, including 170,000 new cases and 99,000 recurrent ones 10.
But there is reason to believe that the true incidence rate (and total number of cases) could be significantly higher, as several studies suggest that these diseases are often undiagnosed. The Worcester study cited above also concluded that more than half of the cases that actually occur are never diagnosed, and therefore as many as 600,000 cases may occur each year 10. Another study found that the diagnosis of PE is often missed; this study of nursing home patients found that the condition was correctly diagnosed before death in only 39 to 50 percent of patients where it was confirmed in an autopsy 11, 12. While the precise incidence and prevalence remain “elusive” 10 and a matter of some debate, one thing is undeniably clear—DVT/ PE are major national health problems that have a dramatic, negative impact on the lives of hundreds of thousands of Americans each year.
There is reason to believe that the magnitude of the problem will increase. Several studies have found that the incidence has remained relatively stable over time 8, 13, although one study found an increased incidence of DVT in hospitalized patients between 1979 and 1999 14. Assuming that the overall incidence remains the same, one would expect the total number of DVT/PE cases to grow at the same rate as overall population growth. However, the incidence of DVT/ PE increases markedly with age. Thus, as the United States population increases in average age, it is quite possible that, in the absence of other influences such as better prevention, the growth in the total number of DVT/PE cases will outpace population growth. Given that DVT/PE are already common and devastating conditions, it is imperative that all stakeholders come together to halt, and hopefully reverse, the growth in the number of cases.
What Are the Consequences of DVT and PE?
DVT and PE together may be responsible for more than 100,000 deaths each year. DVT alone does not frequently result in death; the National Center for Health Statistics reports that it is an underlying or contributing cause of death in over 10,000 cases per year 15. PE is responsible for many more deaths, although estimates of the exact toll are also elusive 10 and vary widely, ranging from just below 30,000 to over 80,000. The most conservative estimates come from studies that review death certificate data. A 20-year review of data from 1979–1998 found that the age-adjusted death rate for PE was 94 per 1,000,000 individuals 16. Extrapolating to today’s population suggests that an estimated 28,200 people die each year from this disease. But as noted previously, PE is often undiagnosed, and thus the true death rate is almost certainly substantially higher. In fact, community-based epidemiological studies suggest that roughly one in five individuals die almost immediately from PE, while 40 percent die within 3 months 17, 18. Applying this 40 percent figure to the 207,000 recognized annual PE cases cited earlier suggests an annual death rate of 82,800.
Another way to estimate the death toll is to look at statistics related to both diseases. An estimated 30 percent of patients die within 3 months 6. Applying this 30 percent figure to the previously cited estimates of between 350,000 and 600,000 cases each year suggests that at least 100,000, and perhaps as many as 180,000, individuals die directly or indirectly as a result of DVT/PE each year.
Many of those who survive will be affected for the rest of their lives. At a minimum, those who have had DVT or PE will remain at increased risk for another episode. (See figure 1). Roughly 30 percent of those who have a DVT in a given year will suffer from a recurrent episode sometime in the next 10 years, with the risk being greatest in the first two years 5, 6, 19, 20. Recurrence is also more likely if the initial episode was “spontaneous”—that is, not provoked by transient (often one-time) events such as trauma, surgery, or hormonal changes due to pregnancy, oral contraceptives, or hormone replacement 4, 5. Patients with symptomatic PE tend to have a higher risk of recurrent VTE than those presenting with DVT symptoms alone. The recurrence in those who initially presented with PE is more likely to be another embolism (as opposed to DVT alone) 21. For reasons that remain unclear, the risk of recurrent VTE is higher among men than women. (See figure 2). 22. To minimize the risk of recurrence, anyone who has had either disease must remain vigilant about avoiding and/or managing the potential impact of other risk factors such as prolonged air travel, surgery, or trauma.
Along with the potential for recurrence, individuals who suffer an initial episode may also experience chronic venous insufficiency (CVI), which is also referred to as postthrombotic syndrome or PTS, with 30 percent suffering from CVI either immediately or within 10–20 years of the initial episode 3, 19, 23. In one cohort of VTE patients followed for 10 years, more than half showed signs of CVI, while six percent developed severe disease 20. CVI occurs when the blood clot injures or destroys one or more of the venous valves that are located in the deep veins of the leg. When functioning properly, these valves work against gravity to help pump blood back to the heart when an individual is sitting or standing. When these valves are either damaged or destroyed, individuals may feel leg pain and experience swelling when standing. They may also develop other unpleasant symptoms, including mild or extensive varicose veins (which are cosmetically unappealing and can cause additional chronic pain and burning), skin breakdown, ulcers, and brownish skin pigmentation changes, which tend to be permanent and irreversible. The most severely affected patients may find that the skin inside their ankles becomes thickened, darkened, and prone to recurrent skin breakdown and painful ulcers (known as venous stasis ulcers) that often do not easily heal. CVI has been found to cause a significant reduction in the quality of life, similar to the impact caused by chronic heart, lung, or arthritic disease 24, 25.
What Factors Raise the Risk for DVT and PE?
There are differential effects by gender, race, and age on individuals with DVT/PE. These diseases also disproportionately effect certain groups of individuals, such as those who:
- have experienced recent trauma
- have undergone major surgery
- are obese
- have cancer
- are pregnant
- use hormone therapy
Age, Gender, and Race-Specific Incidence
Like many diseases, DVT/ PE disproportionately affect the elderly. (See figure 3). The incidence among children (under the age of 14) is quite low, at less than 1 per 100,000 measured in person-years. Incidence rates rise relatively slowly until the age of 50, then accelerate dramatically, reaching 1,000 per 100,000 person-years by the age of 85 8.
Women have a higher incidence of DVT during their child-bearing years although this risk is still relatively low compared to risk levels for older men and women. However, after the age of 50 8, men are at greater risk than women.
For reasons that are not completely understood, African Americans and Caucasians tend to have a greater risk for these conditions than those whose ethnic background is either Asian or Native American. African Americans have a 30 percent higher risk than do Caucasians, while Asian and Native Americans have a 70 percent lower risk 26, 27.
Genetic Factors That Raise Risk
Thrombophilia is an inherited blood clotting disorder caused by one or more genetic risk factors or mutations that make a person susceptible to DVT/ PE. These factors include deficiencies in the anticoagulation factors protein C, protein S, and antithrombin, and mutations in the factor V and prothrombin genes which result in Factor V Leiden and prothrombin G20210A 28 respectively. Over one-third (35 percent) of DVT patients have at least one of these five factors 29, 30. An individual with such a genetic mutation will not necessarily develop these conditions, and fewer than 10 percent of those who carry the most common mutations will develop a detectable blood clot each year 31. But the risks are much greater for those individuals with thrombophilia compared to the population at large, particularly for those who also have another risk, such as surgery, hospitalization, or a prolonged bed stay.
In almost all cases, the presence of an inherited blood clotting disorder in an individual indicates that at least one of the parents also has the disorder, and there is a 50 percent chance that any sibling or child of that individual will have it as well. Other blood relatives, including aunts, uncles, and cousins, may also have the mutation.
Following is a brief description of the most common genetic mutations:
- Factor V Leiden: Factor V Leiden is a relatively common mutation in the gene for clotting factor V that leads to an increased risk of DVT/PE. An estimated 15 to 20 percent of DVT/PE patients have this abnormality 29, 30. This defect is most commonly found among Caucasians (with roughly five percent carrying it) 32, with Asians and Africans rarely carrying the mutation.
- Prothrombin 20210: Roughly two to three percent of Caucasians have a mutation in the gene that produces prothrombin, which is called clotting factor II 33. Approximately six percent of all DVT/PE patients have this mutation, which leads to a three-fold increase in the risk of thrombosis (34)
- Antithrombin, Protein C, and Protein S Deficiency: Mutations in the genes that produce protein C and its cofactor protein S are found in less than one percent of the population, while deficiencies in the gene that produces antithrombin are found in roughly 1 in 5,000 individuals 35, 36.Deficiencies in the natural anticoagulants protein C, protein S, and antithrombin lead to a tenfold increase in risk of thrombosis in an individual who inherits the gene mutation from one parent, with the highest risk in those with antithrombin deficiency 37.
Acquired Factors That Raise Risk
Exposure to steroid hormones—especially estrogen—can raise the risk of developing a blood clot. Thus, women using oral contraceptives in their child-bearing years and postmeno-pausal women who use hormone therapy (HT) are at increased risk. Oral contraceptives that contain both estrogen and progestin increase the risk of a blood clot by two- to eight-fold 38–43. (The risk may even be greater with patches that contain transdermal contraceptives, since the amount of estrogen absorbed can be 60 percent higher 44). An alternative to consider may be contraceptives that use only progestin as these do not appear to increase the risk of DVT or PE 45–47. However, it is important to keep in mind that the absolute risk for women of fertile age who use oral contraceptives is fairly low— 2 to 8 per 10,000 person-years, which is still substantially less than the risk faced by older women and men 48, 49.
A Case Study
This is the story of a college-age girl with a genetic susceptibility to blood clots who experienced an unusual manifestation of venous thrombosis that ultimately claimed her life. Like many young women, she was very self-conscious about her complexion. Her gynecologist explained that one of the beneficial side effects of hormone-based contraceptives is to help clear one’s complexion. So she began taking oral contraceptives and later switched to a patch. While the patch cleared her complexion, she and her parents did not know that she was one of 7,000,000 women in the U.S. with Factor V Leiden, a genetic abnormality that made her much more likely to develop DVT/PE 28. The combination of a genetic predisposition and the use of oral contraceptives proved to be a deadly one, as she developed blood clots in the portal and hepatic veins of her abdomen. (The presence of clots in these locations is not technically classified as DVT, but it is considered a form of venous thrombosis, thus highlighting the fact that VTE can occur anywhere in the body.) After months of suffering from fatigue, nausea, and, ultimately, a markedly swollen abdomen, she died in May 2003 at the age of 21.
Pregnancy increases the risk of DVT fivefold compared to nonpregnancy, with the risk being even greater postpartum 50. DVT can be life-threatening in pregnancy, as pulmonary embolism is the most common cause of maternal death in developed countries 51. Comorbiditites such as obesity and diabetes magnify the existing risk.
Post-menopausal women undergoing HT also have a higher risk of DVT/PE, with recent large studies suggesting a two- to four-fold increase in risk, with even larger increases in risk for those on high doses of estrogen (greater than 1.25 mg/day) 52–55. Women with thrombophilia who also are exposed to oral contraceptives, pregnancy, or HT will face a significantly greater risk than the above statistics suggest 28.
Individuals who develop tumors have a greater tendency to develop blood clots, thus creating increased risk. About 10 percent of patients who present with DVT/PE will have an occult cancer diagnosed within two years of the thrombotic episode 56.
Although all patients with active cancer have an increased risk of DVT/PE, the risk appears to be higher for those with pancreatic cancer, lymphoma, malignant brain tumors, cancer of the liver, leukemia, and colorectal and other digestive cancers. The risk is especially high for patients whose cancer has spread to other parts of the body 57–60. Cancer patients receiving chemotherapy are at even higher risk 57, 61–65. Cancer patients with VTE face much worse outcomes than those with cancer alone. The probability of death within 183 days of initial hospital admission is over 94 percent for those with VTE and malignant disease, compared to less than 40 percent for those with cancer alone. (See figure 4) 66.
The incidence of DVT/PE is substantially higher for cancer patients than for non-cancer patients across all types of major surgery, including neurosurgery, head and neck, vascular, urologic, gastrointestinal, and orthopedic surgeries 67. In the absence of preventive treatment, an estimated 40 to 80 percent of surgical cancer patients will develop DVT in the calf vein while 10 to 20 percent will develop DVT in a proximal vein. Between four and 10 percent of cancer patients undergoing major surgery will develop PE, and one to five percent are fatal 68. Once a cancer patient develops a first episode of VTE, he or she has three times the risk of developing a subsequent episode (compared to noncancer patients) 56.
For reasons that are not entirely clear, people who are obese are at greater risk of DVT/PE. Individuals with a body mass index (BMI)* greater than 30 have a two- to threefold increase in the risk of developing a blood clot, with the risk being even higher for those with a BMI above 40 69–71. The combination of obesity and other risk factors increases the risk even further. For example, obese women on oral contraceptives face a tenfold increase in risk (compared to two- to threefold for nonobese women on oral contraceptives) 71.
The Role of Triggering Events
The majority of DVT/PE events are related to specific, identifiable triggering events such as hospitalization, major surgery, trauma, and prolonged periods of immobility (as can occur in a nursing home or during long flights). It is often the combination of an individual with genetic and/or acquired risk factors who also experience one of these triggering events that leads to the development of a DVT or PE.
Hospitalization for Acute Medical Illness
Hospitalization may be considered the single most important risk factor for developing a DVT/PE. Hospitalization has been shown to raise an individual’s risk of an event as compared to living in the community 61. Much of the increased risk is related to patients who must undergo major surgery (which is discussed separately in the next section). Those who are hospitalized for acute medical illness have more than a tenfold increased risk for VTE 61.
Most hospitalized patients have at least one risk factor, including immobility, cancer, infection, and/or surgery. In fact, in the absence of appropriate preventive treatment, 10 to 40 percent of medical and general surgery patients and 40 to 60 percent of patients requiring major orthopedic surgery develop thrombosis 68. Many of these events are not clinically apparent, but they can potentially lead to later problems, such as PE. In fact, roughly one out of 10 hospital deaths are related to PE, and many times this disease was not suspected before death 72.
A Case Study
July 17, 2005 started out as a normal Sunday for Heidi Blongastainer. She was 36 weeks pregnant and felt tired. She and her husband Brian were heading to her in-laws’ summer cottage in Cape Cod for a barbecue. On their way home, a car driven by a drunk driver who was drag racing crossed the median strip of the highway and hit their car head on while traveling 90 miles per hour. Heidi felt her water break upon impact. She was trapped in the car for approximately 45 minutes, with the dashboard on top of her legs. (Brian suffered only minor injuries and was able to get out of the car and call for help.) After being pried out of the car, Heidi was brought to a small hospital near Cape Cod where they confirmed that her daughter, just a few weeks from being born, did not have a heartbeat. She was then brought to Brigham and Women’s Hospital where she required emergency surgery and remained hospitalized for a week.
After returning home, Heidi had a walker and could walk only very short distances. Her feet and right hip were extremely swollen and bruised, making it difficult for her to move. During the next few days, her feet seemed to get worse, and she started to develop shooting pains in her back whenever she breathed. Thinking that the symptoms were due to cracked ribs, she downplayed them when talking to her doctors.
Her mother warned her about blood clots, but Heidi discounted her advice, not believing that an otherwise healthy 28-year-old woman could develop blood clots due to an automobile accident. Heidi continued to downplay her symptoms at her followup visit with the surgeon. Later in the same week she started to experience shortness of breath and additional pain, soreness, redness, and swelling in her calf and feet. Sitting in bed, she could not catch her breath. That Saturday, 6 days after getting out of the hospital, she developed a fever. She paged her surgeon to tell him about her symptoms, focusing primarily on the pain and swelling in her feet. The surgeon told her to go to the Brigham and Women’s Hospital Department of Emergency Medicine, where she was diagnosed with cellulitis of the leg. But doctors also questioned her about her other symptoms. After hearing her answers, she was immediately taken for a CAT scan to check for blood clots. When the doctor came back, Heidi was informed that she had multiple, large blood clots in her lungs. She was immediately put on anticoagulation therapy, which continued for 6 months. She also participated in a PE support group that met every 3 weeks.
When Heidi presented her story at the Surgeon General’s Workshop only 8 months after her accident she still had pain in her calf and remained anxious about the possibility of developing a new clot (especially since discontinuing anticoagulation medication). But unlike before, she now knows what symptoms to look for and what to do if they develop.
Recent research suggests that certain identifiable subsets of acute medical inpatients are at especially high risk of DVT/PE, including those over the age of 75; those who are obese; and those with any of the following:
- prior history of these conditions
- active cancer
- acute infection
- neurological disease combined with lower extremity weakness
- long-bone fracture
- chronic renal disease
- a prior superficial vein thrombosis
Trauma and Major Surgery
Any injury to body tissues, whether due to surgery or trauma, increases the risk of a blood clot, because the injury stimulates the body’s clotting processes. Blood clots due to trauma and surgery occur relatively quickly, with most developing within two weeks of the event, and some happening much more quickly (within a few hours or even during surgery). DVT/PE also can occur up to several months after surgery or major trauma.
Individuals undergoing certain types of surgery or who experience certain types of trauma are especially prone to blood clots, including those having
- pelvic (gynecological and urological) surgery
- orthopedic surgery (including hip replacement or fracture repair)
- spinal cord paralysis
- multiple limb fractures
- pelvis/hip socket injury.
Nursing Home Residency
Nursing home residents are an often overlooked risk group for DVT/PE, even though they are more than twice as likely as nonresidents of nursing homes to develop these conditions, and they account for over 13 percent of all such events that occur outside the hospital 75.
Any sort of travel has the potential to increase the risk of DVT/PE. Prolonged air, car, and rail trips where the traveler is immobile for long periods of time appear to bring about the greatest risk. In fact, travel by air, car, train, or bus for four or more hours increases the risk about twofold for several weeks after the trip 76. The risk is even greater for travelers with other risk factors.
The Economic Costs of DVT/PE
There are very few data available on the economic costs of VTE, and more research is needed on both the direct and indirect costs to individuals and society at large. As noted earlier, conservative estimates suggest that over 350,000 people are affected by DVT/PE each year, and the vast majority of these individuals will require expensive inpatient treatment. Those who survive the disease may live with a long-term, chronic disorder that is often characterized by repeated episodes that result in additional hospitalizations and treatments. Many individuals with these disorders may also be unable to remain productive members of the workforce (i.e., they may not be able to work at all, may miss work periodically, or may be able to work but at diminished productivity levels), thus creating an economic hardship for their family and diminishing the overall productivity and economic output of the Nation.
BMI is the statistical measure of the weight of a person scaled according to height. In the U.S., BMI is calculated as follows: 703 x (an individual’s body weight in pounds/the square of his or her height in inches).
Office of the Surgeon General (US), Rockville (MD)
Office of the Surgeon General (US); National Heart, Lung, and Blood Institute (US). The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Rockville (MD): Office of the Surgeon General (US); 2008. SECTION I: Deep Vein Thrombosis and Pulmonary Embolism as Major Public Health Problems.