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CHAPTER
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36
The Epidemiology of Venous Thromboembolism
in the Community: Implications for Prevention
and Management
JOHN A. HEIT
INTRODUCTION
The epidemiology of venous thromboembolism (VTE) in
the community has important implications for VTE prevention and management. This chapter describes the incidence,
survival, recurrence, complications, and risk factors for deep
vein thrombosis of the leg, pelvis, or arm, and its complication, pulmonary embolism. The epidemiology of thrombosis
affecting other venous circulations (e.g., cerebral sinus, mesenteric, renal, hepatic, portal) is beyond the scope of this
review. Since population-based studies of venous thromboembolism epidemiology are most generalizeable to the
reader’s individual patients, this chapter focuses on data
provided from studies that included the complete spectrum
of the disease from well-described populations.
THE INCIDENCE OF DEEP
VEIN THROMBOSIS AND
PULMONARY EMBOLISM
The average annual incidence rates of venous thromboembolism among white Americans during the 25-year period,
1966 to 1990 (age- and sex-adjusted to the 1980 U.S. white
population), was 117 per 100,000 person-years.1 The venous
thromboembolism incidence over the more recent seven-year
period, 1991 to 1997 (117.7 per 100,000; similarly adjusted,
but to the 2000 U.S. white population), has not changed signifi cantly compared to the 10-year period, 1981 to 1990
(116.7 per 100,000; see Figure 36.1). Based on the more
recent rates, 249,000 incident venous thromboembolism
cases occur annually among U.S. whites. The incidence
appears to be similar or higher among African-Americans
and lower among Asian- and Native-Americans.
2–6
Assuming
that the 1991 to 1997 age- and sex-specifi c venous thromboembolism incidence among blacks (black- or AfricanAmerican alone) is comparable to whites, and adjusting for
the different age and sex distribution of black-Americans, the
overall age- and sex-adjusted venous thromboembolism incidence was 77.6 per 100,000. Based on this incidence, 27,000
incident venous thromboembolism cases occur annually
among U.S. blacks, for a total of over 275,000 new venous
thromboembolism cases per year in the United States.
Venous thromboembolism is predominantly a disease of
older age.
thrombophilia,10 venous thromboembolism is rare prior to
late adolescence.
thromboembolism incidence rate for persons age 15 years
or older is 149 per 100,000.1 Incidence rates increase exponentially with age for both men and women and for both
deep vein thrombosis and pulmonary embolism (see Figures
36.2 and 36.3).
higher for men (130 per 100,000) than women (110 per
100,000; male : female sex ratio is 1.2 : 1).
are somewhat higher in women during the childbearing
years, whereas incidence rates after age 45 years are generally higher in men. Pulmonary embolism accounts for an
increasing proportion of venous thromboembolism with
increasing age for both genders.
1,7,8
In the absence of a central venous catheter9 or
1,11
The age- and sex-adjusted venous
1,8
The overall age-adjusted incidence rate is
1
Incidence rates
1
SURVIVAL AFTER DEEP
VEIN THROMBOSIS AND
PULMONARY EMBOLISM
Survival after venous thromboembolism is worse
than expected, and survival after pulmonary embolism is
much worse than after deep vein thrombosis alone (see
The Vein Book
323
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Copyright © 2006, Elsevier Inc.
324 Chapter 36/The Epidemiology of Venous Thromboembolism in the Community: Implications for Prevention and Management
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FIGURE 36.1 Age- and sex-adjusted annual incidence of all venous thromboembolism, deep vein thrombosis (DVT)
alone, and pulmonary embolism with or without deep vein thrombosis (PE ± DVT).
FIGURE 36.2 Annual incidence of venous thromboembolism by age and gender.
1
1
FIGURE 36.3 Annual incidence of all venous thromboembolism, deep vein thrombosis (DVT) alone, and pulmonary
embolism with or without deep vein thrombosis (PE ± DVT) by age.
1
Venous Thromboembolism Recurrence 325
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Table 36.1).
12–14
The risk of early death among patients with
symptomatic pulmonary embolism is 18-fold higher compared to patients with deep vein thrombosis alone.12 Pulmonary embolism is an independent predictor of reduced
survival for up to three months. For almost one-quarter of
pulmonary embolism patients, the initial clinical presentation is sudden death. Independent predictors of reduced
early survival after venous thromboembolism include
increasing age, male gender, lower body mass index, confi nement to a hospital or nursing home at venous thromboembolism onset, congestive heart failure, chronic lung
disease, serious neurological disease, and active malig-
8,12,13
nancy.
Additional clinical predictors of poor early survival after pulmonary embolism include syncope and arterial
hypotension.15 Evidence of right heart failure based on clinical examination, plasma markers (e.g., cardiac troponin T,
brain natriuretic peptide)
TABLE 36.1 Survival (%) After Deep Vein Thrombosis vs.
Pulmonary Embolism
Time Deep vein thrombosis alone Pulmonary embolism
0 days 97.0 76.5
7 days 96.2 71.1
14 days 95.7 68.7
30 days 94.5 66.8
90 days 91.9 62.8
1 year 85.4 57.4
2 years 81.4 53.6
5 years 72.6 47.4
8 years 65.2 41.5
16,17
or echocardiography13 predicts
12
poor survival among normotensive pulmonary embolism
patients. Pulmonary embolism patients with these characteristics should receive aggressive anticoagulation therapy, and
possibly thrombolytic therapy in selected cases.
18,19
VENOUS THROMBOEMBOLISM
RECURRENCE
Venous thromboembolism recurs frequently; about 30%
of patients develop recurrence within the next 10 years (see
Table 36.2, Figure 36.4).20 The hazard of recurrence varies
with the time since the incident event and is highest within
the fi rst six to 12 months. However, even at 10 years the
hazard of recurrent venous thromboembolism never falls to
TABLE 36.2 Cumulative Incidence and Hazard of Venous
Thromboembolism Recurrence
Venous thromboembolism recurrence
Time to
recurrence Cumulative recurrence Hazard of recurrence
% Per 1000 person-days (±SD)
0 days 0.0 0
7 days 1.6 170 (30)
30 days 5.2 130 (20)
90 days 8.3 30 (5)
180 days 10.1 20 (4)
1 year 12.9 20 (2)
2 years 16.6 10 (1)
5 years 22.8 6 (1)
10 years 30.4 5 (1)
20
FIGURE 36.4 Cumulative incidence of fi rst venous thromboembolism recurrence (—), and the hazard of fi rst recur-
rence per 1000 person-days (- - -).
20
326 Chapter 36/The Epidemiology of Venous Thromboembolism in the Community: Implications for Prevention and Management
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TABLE 36.3 Independent Predictors of Venous
Thromboembolism Recurrence
Characteristic Hazard ratio 95% CI
Age* 1.17 1.11, 1.24
Body Mass Index† 1.24 1.04, 1.47
Neurologic Disease with Extremity 1.87 1.28, 2.73
Paresis
Active Malignancy
Malignancy with Chemotherapy 4.24 2.58, 6.95
Malignancy without Chemotherapy 2.21 1.60, 3.06
*per decade increase in age.
†per 10 kg/m
2
increase in body mass index.
20
zero. Although active therapeutic anticoagulation is effective in preventing recurrence,
21–23
the duration of anticoagulation does not affect the risk of recurrence once primary
therapy for the incident event is stopped.
24–26
These data
suggest that for a subset of patients, venous thromboembolism is a chronic disease with episodic recurrence; indefi nite
secondary prophylaxis may be warranted for this patient
21–23,26,27
subset.
male gender,
Independent predictors of recurrence include
20,28,29
increasing patient age and body mass
index, neurological disease with extremity paresis, and
active malignancy (see Table 36.3).
dictors include “idiopathic” venous thromboembolism,
a lupus anticoagulant or antiphospholipid antibody,
8,20,30–33
Additional pre-
22,34
22,24,33
antithrombin, protein C or protein S defi ciency,35 and possibly
persistent residual deep vein thrombosis.36 Prolonged secondary prophylaxis with anticoagulation therapy should be
considered for patients with these characteristics. Although
the incident event type (deep vein thrombosis alone vs. pulmonary embolism) is not a predictor of recurrence, patients
with recurrence are signifi cantly more likely to recur with
the same event type as the incident event type.
37,38
Because
the seven-day case fatality rate is signifi cantly higher for
recurrent pulmonary embolism (34%) compared to recurrent
deep vein thrombosis alone (4%),38 prolonged anticoagulation should be considered for incident pulmonary embolism,
especially for patients with chronically reduced cardiopulmonary functional reserve.
COMPLICATIONS OF VENOUS
THROMBOEMBOLISM
The major complications of venous thromboembolism
are venous stasis syndrome (e.g., post-thrombotic syndrome,
including dependent leg swelling and pain, stasis pigmentation and dermatitis, and dermatoliposclerosis) and venous
ulcer, and chronic thromboembolic pulmonary hypertension. The overall incidence of venous stasis syndrome and
venous ulcer is 76.1 and 18.0 per 100,000 person-years,
respectively.39 Venous thromboembolism patients have a 17-
fold increased risk of venous stasis syndrome.39 The 20-year
cumulative incidence of venous stasis syndrome after venous
thromboembolism and after proximal deep vein thrombosis
are about 25% and 40%, respectively.
32,40
Risk factors for
venous stasis syndrome include the venous thromboembolism event type (deep vein thrombosis, with our without
pulmonary embolism) and deep vein thrombosis location
(proximal deep vein thrombosis). The 20-year cumulative
incidence of venous ulcer is 3.7%.40 The risk for venous
ulcer is increased 30% per decade of age at the incident
venous thromboembolism.40 Venous thromboembolism
accounts for about 12% of all venous stasis syndrome occurring in the community.
39
The incidence of chronic thromboembolic pulmonary
hypertension over the 21-year period, 1976 to 1996, was 6.5
per million person-years.41 Over this same time period, the
incidence of acute pulmonary embolism was 485.6 per
million person-years. Thus, the vast majority of acute pulmonary emboli do not progress to chronic thromboembolic
pulmonary hypertension. Applying these incidence rates to
the 2000 U.S. white population, approximately 1367 new
chronic thromboembolic pulmonary hypertension cases
occur in the United States annually.
RISK FACTORS FOR VENOUS
THROMBOEMBOLISM
In order to improve survival, avoid recurrence, prevent
complications, and reduce health care costs, the occurrence
of venous thromboembolism must be reduced. To reduce
venous thromboembolism incidence, persons at risk for
venous thromboembolism fi rst must be identifi ed. Independent risk factors for venous thromboembolism include
patient age, surgery, trauma, hospital or nursing home
confi nement, active malignant neoplasm with or without
concurrent chemotherapy, central vein catheterization or
transvenous pacemaker, prior superfi cial vein thrombosis,
varicose veins among the young, and neurological disease
with extremity paresis; patients with chronic liver disease
have a reduced risk (see Table 36.4).
VTE increases signifi cantly with age for both idiopathic and
secondary VTE, suggesting that the risk associated with
advancing age may be due to the biology of aging rather
than simply an increased exposure to VTE risk factors with
advancing age.44 Compared to residents in the community,
hospitalized residents have over a 150-fold increased incidence of acute venous thromboembolism.45 Hospitalization
and nursing home residents together account for almost 60%
of incident venous thromboembolism events occurring in
46
the community.
Thus, hospital confi nement provides an
important opportunity to signifi cantly reduce venous thromboembolism incidence. Of note, hospitalization for medical
illness and hospitalization for surgery account for almost
42,43
The incidence of
The Genetic Epidemiology of Venous Thromboembolism 327
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TABLE 36.4 Independent Risk Factors for Deep Vein
Thrombosis or Pulmonary Embolism
Baseline characteristic Odds ratio 95% CI
Institutionalization with or without
recent surgery
Institutionalization without 7.98 4.49, 14.18
recent surgery
Institutionalization with 21.72 9.44, 49.93
recent surgery
Trauma 12.69 4.06, 39.66
No malignancy 1.0
Malignancy without chemotherapy 4.05 1.93, 8.52
Malignancy with chemotherapy 6.53 2.11, 20.23
Prior central venous catheter or 5.55 1.57, 19.58
transvenous pacemaker
Prior superfi cial vein thrombosis 4.32 1.76, 10.61
Neurologic disease with 3.04 1.25, 7.38
extremity paresis
Serious liver disease 0.10 0.01, 0.71
42
equal proportions of venous thromboembolism (22% and
24%, respectively), emphasizing the need to provide prophylaxis to both of these risk groups. Nursing home residents independently account for over one-tenth of all venous
thromboembolism disease in the community.
46
The risk among surgery patients can be further stratifi ed
based on patient age, type of surgery, and the presence of
active cancer.
47,48
The risk of postoperative venous thromboembolism increases with advancing patient age,49 especially
for surgery patients that are 65 years of age or older.48 Highrisk surgical procedures include neurosurgery, major
orthopedic surgery of the leg, thoracic, abdominal or pelvic
surgery for malignancy, renal transplantation, and cardiovascular surgery.48 Obesity
49–51
and poor American Society of
Anesthesiology physical status51 are risk factors for venous
thromboembolism after total hip arthroplasty. Other independent risk factors for VTE after major surgery (after controlling for active cancer) include intensive care unit (ICU)
length of stay greater than six days, immobility, and infection.49 The risk from surgery may be less with neuraxial
(spinal or epidural) anesthesia compared to general anesthesia.52 Risk factors for VTE among patients hospitalized for
acute medical illness may include active cancer and prior
VTE.53 After controlling for active cancer, additional independent risk factors include increasing patient age and body
mass index (BMI), prior superfi cial vein thrombosis, chronic
renal disease, neurological disease with extremity paresis,
fracture and immobility,54 and possibly infection.
53
Active cancer accounts for almost 20% of incident venous
thromboembolism events occurring in the community.46 The
risk appears to be higher for patients with pancreatic cancer,
lymphoma, malignant brain tumors, cancer of the liver, leukemia, and colorectal and other digestive cancers.
55,56
Cancer
patients receiving immunosuppressive or cytotoxic chemotherapy are at even higher risk for venous thromboembo-
lism,42 including therapy with l-asparaginase, thalidomide,
or tamoxifen.
A central venous catheter or transvenous pacemaker now
accounts for 9% of incident venous thromboembolism
occurring in the community.46 Prior superfi cial vein thrombosis is an independent risk factor for subsequent deep vein
thrombosis or pulmonary embolism remote from the episode
of superfi cial thrombophlebitis.42 The risk of deep vein
thrombosis imparted by varicose veins is uncertain and
appears to vary by patient age.42 Long haul (>6 hour) air
travel is associated with a slightly increased risk for venous
thromboembolism that is preventable with elastic stockings.57 Coenzyme A reductase inhibitor (statin) therapy
may provide a 20 to 50% risk reduction for venous thromboembolism.58 However, the risk associated with atherosclerosis, or other risk factors for atherosclerosis, remains
uncertain.
59–61
Body mass index, current or past tobacco
smoking, chronic obstructive pulmonary disease, and renal
failure are not independent risk factors for venous thromboembolism after controlling for other risk factors (e.g.,
surgery, hospitalization, trauma).42 The risk associated with
congestive heart failure, independent of hospitalization, is
42,43
low.
Among women, additional risk factors for venous
thromboembolism include oral contraceptive use and
hormone therapy62 and therapy with the selective estrogen
receptor modulator, raloxifene, and pregnancy and the postpartum period.
43,63
Compared to nonpregnant women of
childbearing age, the VTE risk among pregnant women is
increased over four-fold.64 The annual VTE incidence is
fi ve-fold higher among postpartum compared to pregnant
women (511.2 versus 95.8 per 100,000), and the incidence
of DVT is three-fold higher than PE (151.8 versus 47.9 per
100,000). PE is relatively uncommon during pregnancy
compared to postpartum (10.6 versus 159.7 per 100,000).
Other conditions associated with venous thromboembolism include heparin-induced thrombocytopenia, myeloproliferative disorders (especially polycythemia rubra vera
and primary thrombocythemia), intravascular coagulation
and fi brinolysis/disseminated intravascular coagulation
(ICF/DIC), nephrotic syndrome, paroxysmal nocturnal
hemoglobinuria, thromboangiitis obliterans (Buerger’s
disease), thrombotic thrombocytopenic purpura, Bechet’s
syndrome, systemic lupus erythematosus, infl ammatory
bowel disease, Wegener’s granulomatosis, homocystinuria,
and possibly hyperhomocysteinemia.
65,66
THE GENETIC EPIDEMIOLOGY OF
VENOUS THROMBOEMBOLISM
Recent family-based studies indicate that venous thromboembolism is highly heritable and follows a complex mode
of inheritance involving environmental interaction.
Inherited reductions in plasma natural anticoagulants (e.g.,
67–69
328 Chapter 36/The Epidemiology of Venous Thromboembolism in the Community: Implications for Prevention and Management
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antithrombin, protein C, or protein S) have long been recognized as uncommon but potent risk factors for venous
thromboembolism.
70,71
More recent discoveries of impaired
downregulation of the procoagulant system (e.g., activated
protein C resistance, Factor V Leiden),
72–74
increased plasma
concentrations of procoagulant factors (e.g., factors I [fi brinogen], II [prothrombin], VIII, IX, and XI)
basal procoagulant activity,
80–82
impaired fi brinolysis,83 and
75–79
and increased
altered innate immunity84 have added new paradigms to the
list of inherited or acquired disorders predisposing to thrombosis (thrombophilia). These plasma hemostasis-related
factors or markers of coagulation activation both correlate
with increased thrombotic risk and are highly heritable.
85–89
Inherited thrombophilias interact with such clinical risk
factors (e.g., environmental risk factors) as oral contraceptives,90 pregnancy,91 hormone therapy,92 and surgery93 to
increase the risk of incident venous thromboembolism. Similarly, genetic interaction increases the risk of incident94 and
recurrent venous thromboembolism.
95–99
These fi ndings
support the hypothesis that an acquired or familial thrombophilia may predict the subset of exposed persons who
actually develop symptomatic venous thromboembolism.
Although the clinical utility of diagnostic testing for an
inherited or acquired thrombophilia remains controversial,
such studies hold the potential for further stratifying individual patients in to high- and low-risk for incident and
recurrent venous thromboembolism, targeting prophylaxis
to those who would benefi t most, and, ultimately, reducing
the occurrence of venous thromboembolism.
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CHAPTER
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37
Fundamental Mechanisms in Venous Thrombosis
CHRISTOPHER LONGO and THOMAS W. WAKEFIELD
INFLAMMATION AND
VENOUS THROMBOSIS
Rationale
Venous thromboembolic disease represents an ideal
opportunity for advancing our understanding of infl ammation within the vascular system. A great deal of progress has
been made in the interdependent fi elds of selectin, microparticle, phospholipid, and platelet biology in recent years.
Much of this knowledge has been acquired through the utilization of models of venous thrombosis and the compilation
of data from patients with deep vein thrombosis. Present
therapy directed at venous thromboembolic disease (VTE)
relies on anticoagulation strategies with their associated risk
of severe bleeding complications. Our work is directed
toward developing and testing new, targeted therapies for
VTE that will be safer and more effective. These therapies
will exploit new knowledge of the infl ammatory mechanisms leading to venous thrombosis.
Background
Deep vein thrombosis (DVT) and its acute and chronic
sequelae are a signifi cant source of morbidity, mortality, and
cost to the American public. American Heart Association
statistics document two million cases of DVT each year with
the incidence of DVT increasing as the population ages.1
Pulmonary embolus (PE) accounts for 200,000 deaths each
year, and the annual cost of the treatment of VTE is measured in billions of dollars.
noted in one percent of all medicare inpatient discharges.
Chronic venous insuffi ciency (CVI) is a late complication
of DVT suffered by nearly seven million Americans. The
2
We have found that VTE is
3
20-year incidence of CVI is 28% following deep vein thrombosis, although some have suggested the incidence is higher.
The symptoms include swelling, discomfort, and skin
changes ranging from stasis pigmentation to frank ulceration
requiring chronic wound care.
pulmonary hypertension (CTPH) has a two-year incidence
of 3.8% following PE, leading to severe debilitation and
high mortality.
Anticoagulation is the keystone of contemporary therapy
for VTE but carries a signifi cant risk of severe bleeding. Ten
percent of patients suffer minor to moderate hemorrhagic
complications each year, and the annual incidence of lifethreatening hemorrhage is 2%.
plications on heparin therapy is dose dependent, with a 7%
increase in risk for each 10-second increase in the aPTT
value.8 Data from early studies revealed a lower incidence
of bleeding complications with low molecular weight heparin
versus unfractionated heparin, but recent studies have
demonstrated no signifi cant difference.9 The risk of a major
bleeding complication in the fi rst three months of treatment
with heparin initially followed by coumadin is 3%, with a
signifi cantly higher incidence in cancer patients.10 The incidence of major bleeding complications in patients on coumadin maintained with an INR of 2.0–3.0 is half that of
someone maintained with an INR of more than 3.0. Coumadin can be diffi cult to dose, and variability in the INR is
independently associated with an increased frequency of
hemorrhage.
Patients managed with present optimal therapy have a
20% incidence of thrombus extension or recurrence.
Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) can complicate both unfractionated and low
molecular weight heparin therapy resulting in arterial and
venous thrombotic complications.13 Heparin-based therapies
5
11
4
Chronic thromboembolic
6,7
The risk of bleeding com-
12
The Vein Book
331
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