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Acute Deep Venous Thrombosis: Epidemiology and Natural History
Acute venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), are the most common preventable causes of hospital death and a source of substantial long-term morbidity. The impact on health is so great that the Surgeon General of the United States issued a “Call to Action” to combat VTE. An understanding of the risk factors and natural history of VTE is essential in guiding prophylaxis, diagnosis, and treatment. In addition, recognizing underlying risk factors and the multifactorial nature of VTE may aid in the identification of situations likely to provoke thrombosis in both high-risk individuals and those with unexplained thromboembolism. Furthermore, understanding the natural history of VTE is important in defining the relative risks and benefits of anticoagulation, as well as the duration of treatment in individual patients.
Epidemiology
Incidence
The incidence of recurrent, fatal, and nonfatal VTEs is estimated to exceed 900,000 cases annually in the United States alone. A 35-year population-based study using the Rochester Epidemiology Project database of Olmsted County, MN demonstrated an overall average age- and sex-adjusted annual VTE incidence of 122 per 100,000 person-years (DVT, 56 per 100,000; PE, 66 per 100,000). This study also demonstrated higher age-adjusted rates among men than women (134 vs. 115 per 100,000, respectively). First-time VTEs are approximated to occur in 250,000 US white individuals annually. When compared with other racial populations, Whites have a lower incidence of VTE than do African Americans (104 vs. 141 per 100,000) and a higher incidence of VTE than do Hispanics and Asian/Pacific Islanders combined (104 vs. 21 per 100,000). However, the problem of VTE is not just isolated to the United States; it is a global issue. The estimates of VTE across the European Union were 684,019 cases of DVT, 434,723 cases of PE, with 543,454 VTE-related fatalities.
Populations Affected
The incidence of VTE varies with the population studied, use of thromboprophylaxis, the intensity of screening, and the accuracy of the diagnostic test employed. For example, individuals with acute spinal cord injury who were screened systematically with venography demonstrated DVT at a rate of 81%. However, medical–surgical intensive care unit (ICU) patients who received thromboprophylaxis had a DVT rate reported at 10% to 18%, compared with those who were not given DVT prophylaxis having a rate of 25% to 32%. , Interestingly, the risk of VTE in the critically ill patient population is not limited to the time actually spent in the ICU. A single-center study showed that of the VTEs diagnosed in the critically ill, 64% were diagnosed with a VTE after discharge from the ICU. It is suggested that prolonged immobility after discharge from the ICU may have contributed to the high rate of DVT. Similarly, prolonged immobility contributes to increased rates of VTE in nursing home residents. In summary, it appears that medical–surgical ICU patients are at lower risk for DVT compared with acute spinal cord injury, trauma, or neurosurgery patients, but at a comparable risk to patients who have had major orthopedic surgery, and at higher risk than medical–surgical ward patients. , Furthermore, a more recent study noted a high (15.2%) rate of DVT in critically ill trauma patients within the first week that did not vary regardless of whether or not prophylaxis was used.
The importance of viral infection on VTE risk is also a timely and important topic. Patients who were critically ill with H1N1 influenza infections had a 23.3-fold higher incidence of PE and a 17.9-fold higher incidence of DVT than critically ill patients without H1N1 influenza. Additionally, moderate intensity infusion of systemic heparin anticoagulation provided significant protection from thrombotic events in the critically ill patients with H1N1 but not those without H1N1 influenza infection. Early data suggests a similarly high risk of VTE in patients with COVID-19 and potential benefits of heparin prophylaxis. However, the optimal dose of heparin prophylaxis or treatment for patients with COVID-19 remains unknown at this time, and whether it is better to use systemic heparin or low-molecular-weight heparin.
Risk Factors
DVT occurring in the setting of a recognized risk factor is often defined as a secondary event, whereas those that occur in the absence of risk factors is termed primary or idiopathic. Known risk factors for DVT are listed in Table 146.1 . However, use of the terms “provoked,” “unprovoked,” and “idiopathic” may no longer be as relevant as they once were given changes in recommended treatments for patients with VTE. Rather, the emphasis has begun to shift towards identifying reversible risk factors whenever possible. The high incidence of acute DVT in hospitalized patients, the availability of objective diagnostic tests, and the existence of clinical trials evaluating prophylactic measures have helped to more readily identify high-risk groups in this population compared with the outpatient population. Malignancy, surgery, and trauma within the previous 3 months remain significant risk factors for outpatient thrombosis, whereas the prevalence of surgery and malignancy is higher among inpatients with DVT. , Approximately 47% of outpatients with a documented DVT have one or more recognized risk factors. The incidence of VTE proportionally increases with the number of risk factors. The 2005 Caprini score is currently the most widely utilized system in the country for surgical cases ( Fig. 146.1 ) , while other scores are more common for medical patients. These include the Padua score and the IMPROVE score, both of which have been externally validated but with only moderate discriminatory ability (see Ch. 20 , Clinical Evaluation of the Venous and Lymphatic Systems).
TABLE 146.1
Risk Factors for Acute Deep Venous Thrombosis and Pulmonary Embolism
Modified from Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med . 2000;160:809.
| Risk Factor for DVT or PE | Odds Ratio | 95% Confidence Interval |
|---|---|---|
| Hospitalization | ||
| With recent surgery | 21.72 | 9.44–49.93 |
| Without recent surgery | 7.98 | 4.49–14.18 |
| Trauma | 12.69 | 4.06–39.66 |
| Malignant Neoplasm | ||
| With chemotherapy | 6.53 | 2.11–20.23 |
| Without chemotherapy | 4.05 | 1.93–8.52 |
| Prior central venous catheter or pacemaker | 5.55 | 1.57–19.58 |
| Prior superficial vein thrombosis | 4.32 | 1.76–10.61 |
| Neurologic disease with extremity paresis | 3.04 | 1.25–7.38 |
| Varicose Veins | ||
| Age 45 years | 4.19 | 1.56–11.30 |
| Age 60 years | 1.93 | 1.03–3.61 |
| Age 75 years | 0.88 | 0.55–1.43 |
| Congestive Heart Failure | ||
| Thromboembolism not categorized as a cause of death at postmortem | 9.64 | 2.44–38.10 |
| Thromboembolism categorized as a cause of death at postmortem | 1.36 | 0.69–2.68 |
DVT, deep venous thrombosis; PE, pulmonary embolism.
Age
VTE occurs at all ages, although a higher incidence has consistently been associated with advanced age. In a community-based study of phlebographically documented DVT, the yearly incidence of DVT was noted to increase progressively from almost 0 in childhood to 7.65 cases per 1000 in men and 8.22 cases per 1000 in women older than 80 years. The incidence of DVT increased 30-fold from those age 30 years to those older than 80 years. Rosendaal similarly noted an incidence of 0.006 per 1000 children younger than 14 years, which rose to 0.7 per 1000 among adults 40 to 54 years old. Furthermore, Hansson and colleagues found the prevalence of objectively documented thromboembolic events among men increased from 0.5% at age 50 years to 3.8% at age 80 years.
The influence of age on the incidence of VTE is likely multifactorial. The number of thrombotic risk factors increases with age, with three or more risk factors being present in only 3% of hospitalized patients younger than 40 years but in 30% of those 40 years and older. Interestingly, it also appears that the number of risk factors required to precipitate thrombosis decreases with age. This may be related to an acquired prothrombotic state associated with aging as higher levels of thrombin activation markers are found among older people. Advanced age also has been associated with anatomic changes in the soleal veins and more pronounced stasis in the venous valve pockets. ,
Venous diseases, including VTE, are rare in young children, with an incidence of 0.006 per 1000 children younger than 14 years. The incidence of VTE in hospitalized children younger than 18 years has been estimated to be 0.05%. Early mobilization and discharge may partially explain the lower incidence in children. However, the diagnosis is often not considered in pediatric patients, and few studies have systematically evaluated children for DVT. Over time the number of recognized cases in hospitalized children has increased from 0.3 to 28.8 per 10,000 from 1992 to 2005.
VTE in children is almost always associated with recognized thrombotic risk factors, , and multiple risk factors are often required to precipitate thrombosis. DVT may occur in as many as 3.7% of pediatric patients immobilized in halo-femoral traction for preoperative treatment of scoliosis, 4% of children hospitalized in the ICU, and 10% of children with spinal cord injuries. , Symptomatic postoperative DVT is regarded as unusual in children, although there are few data from studies using routine surveillance, and autopsy-identified PE is approximately four times more frequent in pediatric patients who have undergone surgery than in the general pediatric medical population. Other thrombotic risk factors in hospitalized children are local infection and trauma, immobilization, inherited hypercoagulable states, oral contraceptive use, lower limb paresis, and the use of femoral venous catheters. Outpatient DVT is often associated with a prior DVT and thrombophilia.
Immobilization
Immobilization is a risk factor for VTE. Stasis in the soleal veins and behind the valve cusps is worsened by inactivity of the calf muscle pump, which is associated with an increased risk of DVT. The prevalence of lower extremity DVT in autopsy studies also parallels the duration of bed rest, with an increase during the first 3 days of confinement and a rapid rise to very high levels after 2 weeks. DVT was found in 15% of patients dying after 0 to 7 days of bed rest, in comparison with 79% to 94% of those dying after 2 to 12 weeks. Preoperative immobilization is also associated with a twofold increase in risk of postoperative DVT, and DVT among stroke patients is significantly more common in paralyzed or paretic extremities (53% of limbs) than in nonparalyzed limbs (7%). Patients with neurologic disease and extremity paresis or plegia have a threefold higher risk for DVT and PE, which appears to be independent of hospital confinement.
Travel
Immobilization as a thrombotic risk factor extends to include prolonged travel, particularly the “economy class syndrome,” which occurs in people who have sat in a cramped position during extended aircraft flights. Several case series have reported the occurrence of PE in relation to extended travel, although none has rigorously examined the prevalence relative to that of the general population, and few have thoroughly reported the presence of other risk factors. A high prevalence of preexisting venous disease and other thrombotic risk factors in this group of patients has sometimes been noted. , The question of prolonged travel as a risk factor is moderated by observations that extreme duration of venous stasis alone may fail to produce thrombosis and that no consistent rheologic or prothrombotic changes have been demonstrated during prolonged travel. , However, PE is the second leading cause of travel-related death, accounting for 18% of 61 deaths in one study, suggesting that a relationship cannot be excluded.
More evidence of a possible relationship between travel and DVT and PE has accumulated. In a case–control study, Ferrari and associates found that long distance travel increased the risk of DVT, with an odds ratio (OR) of 4.0, and Samama made similar observations (OR, 2.3). Scurr and colleagues found a 10% risk of calf DVT in patients who traveled without compression stockings. Lapostolle and coworkers observed that over an 86-month period, 56 of 135.3 million airline passengers had severe PE. The frequency among those who traveled more than 5000 km (∼3100 miles) was 150 times as high as those who traveled less than 5000 km. In another case–control study, Paganin and associates observed a high incidence of VTE in patients with risk factors for DVT who traveled long distances: in particular, a history of previous VTE (OR, 63.3), recent trauma (OR, 13.6), presence of varicose veins (OR, 10), obesity (OR, 9.6), immobility during flight (OR, 9.3), and cardiac disease (OR, 8.9) increased the risk of DVT. These investigators concluded that low mobility during flight was a modifiable risk factor for development of PE and that travelers with risk factors should increase their mobility.
After a consensus meeting, the World Health Organization published the following conclusions: (1) an association probably exists between air travel and DVT; (2) such an association is likely to be small and mainly affects passengers with additional risk factors for VTE; and (3) similar links may exist for other forms of travel. The available evidence does not permit an estimation of actual risk. Even space flight has now been associated with the development of venous thrombosis, with an obstructive jugular vein thrombosis developing 2 months into a 6-month space mission on the space station.
History of Venous Thromboembolism
Approximately 23% to 26% of patients presenting with acute DVT have a previous history of thrombosis, , and histologic studies confirm that acute thrombi are often associated with fibrous remnants of previous thrombi in the same or nearby veins. Depending on sex and age, population-based studies have demonstrated that recurrent VTE occurs in 2% to 9% of cases.
The risk of recurrent VTE is higher among patients without identifiable risk factors for DVT. In addition, primary hypercoagulability appears to have a significant role in many recurrences. Heterozygous factor V Leiden mutation, which is found in up to 5% of Caucasians and 1%–2% of African and Hispanic Americans, is associated with a four-time greater risk of initial VTE event than the general population. This is even greater in patients with homozygous mutations; however, this is quite rare. Interestingly, factor V Leiden does not seem to have a clinically significant association with VTE recurrence risk, limiting its utility for testing in patients after an initial VTE event. Other identified thrombophilias include inherited conditions (e.g., prothrombin gene mutation, protein C or S deficiency, and antithrombin deficiency) and acquired thrombophilias (e.g., anti-phospholipid antibody syndrome, paroxysmal nocturnal hemoglobunuria, malignancy). Of the inherited thrombophilias, those with the greatest VTE risk are also the least prevalent, including protein C or S deficiency and antithrombin deficiency, each of which is found in <0.5% of the population. , The presence of antiphospholipid antibodies alone, which can be found in up to 5% of the general population, do not necessarily qualify for the diagnosis of the antiphospholipid antibody syndrome. This diagnosis requires confirmation of persistently elevated laboratory markers in the clinical setting of a VTE or other related thrombotic events.
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