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Epidemiology of acute deep vein thrombosis
Epidemiology of Acute Deep Vein Thrombosis Christopher M. Bulger, MD, Chad Jacobs, MD, and Nilesh H. Patel, MD, FSIR
Although the factors leading to venous thrombosis have been known for over a century, Virchow’s initial model of thrombosis has been extensively refined. Activated coagulation is now recognized to be of primary importance in venous thrombogenesis; the concept of venous injury has been expanded to include molecular changes in the endothelium; and stasis has been redefined as a largely permissive factor. Furthermore, it is now clear that venous thrombi undergo a dynamic evolution beginning early after their formation. The natural history of acute deep venous thrombosis (DVT) is a balance between recurrent thrombotic events and processes that restore the venous lumen, both of which have important implications for the development of complications. Although pulmonary embolism (PE) is clearly the most life threatening complication of acute DVT, the long term socio-economic consequences of the post thrombotic syndrome (PTS) have perhaps been underemphasized in clinical trials. The development of post-thrombotic manifestations is related to both residual venous obstruction and valvular incompetence. Recognition of the factors contributing to a poor outcome, including recurrent thrombotic events, the rate of recanalization, the global extent of venous reflux, and the anatomic distribution of reflux and obstruction is important, as there may be therapeutic alternatives to alter the natural history of acute DVT. The treatment alternatives will continue to expand with the introduction of new therapeutic drugs, for both systemic and catheter-directed therapy, and mechanical thrombectomy devices. The primary care physician is challenged with the task of correctly evaluating deep vein thrombosis and providing his patient with access to the most clinically appropriate, and cost-effective, diagnostic and management options available. This article will review the epidemiology of DVT, its risk factors and major complications. © 2004 Elsevier Inc. All rights reserved.
here are several U.S. studies that have examined the epidemiology of acute deep venous thrombosis (DVT). In the Tecumseh Community Health Study, a study on healthy volunteers, Coon found an annual DVT incidence of 122 per 100,000.1 Anderson performed a community-wide study in 16 short-stay hospitals in Worcester, Mass over 1 year and found an average annual incidence of 48 per 100,000.2 Silverstein performed a population based study in Olmstead County, MN, from 1966 to 1990 and found an overall average incidence of acute DVT in 48 per 100,000 per year.3 Kniffin reviewed Medicare claims from 1986 to 1989 and found an annual incidence of acute DVT of 1.8 per 1000 in the age group of 65 to 69 years old.4 White studied the California Patient Discharge Data Set
T
From the Section of Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, and Section of Vascular Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL. Address reprint requests to Nilesh H. Patel, MD, Affiliated Radiologists, SC, 1725 West Harrison Street, Suite 456, Chicago, IL 60612. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0002$30.00/0 doi:10.1053/j.tvir.2004.02.001
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from 1991 to 1994 and found an annual incidence of acute DVT of 230 per 1000,000 in Caucasians above the age of 18.5 The estimated incidence of clinically recognized acute DVT in the US is about 116,000 to over 250,000 new cases per year.1,2
Risk Factors As initially described by Virchow, three factors are of primary importance in the development of venous thrombosis: (1) abnormalities of blood flow, (2) abnormalities of blood, and (3) vessel wall injury.8 Recent advances in coagulation and vascular biology have redefined the importance of Virchow’s model. Not all components of Virchow’s triad are of equal importance in all patients. Several of the currently identified risk factors for acute DVT can be related to one or more of these elements (Table 1). The risk of DVT increases with age, with a relative risk of 1.9 per 10 year increase.9 Other factors that increase DVT risk include trauma (13-fold), surgery (6- to 22-fold), malignancy (5-fold), oral contraceptive use (2- to 4-fold), and lupus anticoagulant (6-fold).9-13 It is now recognized that DVT arise from the interaction of multiple inherited and acquired risk factors. Rosendaal promoted that this complex interaction be referred to as “thrombotic potential.”14 When the cumulative thrombotic potential of all risk factors exceeds a certain threshold, clinical thrombosis is likely. This theory is supported by the observation that the risk of DVT increases with the number of risk factors present.2,15 The general population of hospitalized patients has an average of 1.5 risk factors per patient, with 26% having three or more risk factors.9,16 Three or more risk factors are present in 30% of out-patients with DVT.2,9,15 In symptomatic outpatients, the odds ratio for DVT increases from 1.26 for one risk factor to 3.88 for three or more risk factors.9,15 These risk factors may act synergistically to increase the risk of DVT dramatically above the sum of the individual factors. The thromboembolic risk of surgery has been estimated to be 1.6%, and the risk associated with antithrombin deficiency to be 0.8% per year, respectively. The thromboembolic risk of patients with both risk factors (surgery, antithrombin deficiency) has been estimated to be 12.7% per year.17 Likewise, the use of third generation oral contraceptives may act synergistically with the Factor V Leiden mutation, increasing thromboembolic risk 30- to 50-fold.18-20
Age, Gender, and Race DVT is rare in children but exponentially increases in incidence between the age of 20 and 80 years (Fig 1).2 Kniffin found the annual rate of DVT increased from 1.8 per 1000 at age 65 to 69 years to 3.1 by age 85 to 99 years.4 The increase in calculated cumulative probability of venous thromboembolism (VTE) approaches 10.7% by age 80.11,21,22 The increase risk of DVT with
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 50-54
Surgery
TABLE 1. Risk Factors for Acute DVT Risk Factor
Hypercoagulability
Stasis
Venous Injury
Age Immobilization Surgery Trauma Malignancy Primary Hypercoagulable States (antithrombin III deficiency, Protein C and Protein S deficiency, Factor V Leiden, Prothrombin 20210A, Increase Factor VIII, Hyperhomocysteinemia) History of DVT Family History Oral Contraceptives Estrogen Replacement Pregnancy and Puerperium Antiphospholipid Antibodies (lupus anticoagulant and anticardiolipin antibody) Central Venous Catheters Inflammatory Bowel Disease Obesity Myocardial Infarction/CHF Varicose Veins
X
X X X X
X
X X X X
X X X X X X
Patients undergoing surgery are subject to a 6- to 22-fold increase in risk for DVT. Abdominal, pelvic, orthopedic, neurosurgical, and oncologic surgeries place patients at the highest risk because of immobilization, secondary venous stenosis, and endothelial damage.17 Of note, type of anesthesia has not been identified as an independent risk factor for DVT.29 In addition to immobilization, stasis, and endothelial damage promoting DVT, surgery has been associated with activated coagulation and transient depression of fibrinolysis. An increase in thrombin activation as well as elevated levels of plasminogen activator inhibitor-1 (PAI-1) during the perioperative period have been described.30
Immobilization X
X X X X X
advanced age is likely related to multiple age associated factors including an increased number of major thrombotic risk factors, an acquired prothrombotic state as suggested by increased levels of thrombin activation markers, and changes in the venous system associated with increased stasis.23 Silverstein reported minor gender differences in a large population DVT study, with 50 DVT per 100,000 women and 47 DVT per 100,000 men.3 Furthermore, they noted that the incidence was somewhat higher among women of childbearing age, however, in older age groups the incidence was generally higher among men. Some have not found a significant difference in the incidence of DVT between men and women, while others have noted a slightly increased risk in males (relative risk 1.4).2,15,24 In a California study by White, the annual incidence of DVT per 100,000 was 23 in Caucasians, 29.3 in African Americans, 13.9 in Hispanics, and 6 in Asians and Pacific Islanders.5 Others have found no differences in the incidence of DVT between African Americans and Caucasians.4,25 Racial and ethnic differences in genetic risk factors, including blood group and the factor V Leiden mutation, do exist and may account for the differences in rates of DVT.5,26,27
Before the use of DVT prophylaxis, the autopsy incidence of lower extremity thrombosis was noted to increase within 3 days of bedrest. This rose rapidly to 15% at 1 week, 77% at 2 weeks and 94% at 4 weeks of confinement.31 The importance of immobilization is further emphasized by the observations that thrombosis following bedrest is frequently bilateral while that associated with stroke is often confined to the paralyzed limb. The relationship between DVT and prolonged travel has been controversial; however, there is one case control study that showed an association between DVT and travel of greater than 4 hours duration.32
Malignancy Malignancy increases the risk of DVT by direct tumor compression of the veins, invasion of the vessels causing endothelial damage, and increased secretion of procoagulant factor VIII and fibrinogen.33,34 DVT may complicate 19% to 30% of malignancies with idiopathic thrombosis present in 3% to 23% of patients a the time of diagnosis or may develop 1 to 2 years after
Trauma Trauma patients are subject to a 13-fold increase in risk for DVT. This risk can be attributed to release of vasoactive amines and intimal injury. Unfortunately, the risk from the trauma is compounded by the fact that many of these patients have neurologic and orthopedic injuries resulting in prolonged immobility and venous stasis, which will impart additional risk. Factors identified as important determinants of DVT in this population have included advanced age, blood transfusion, surgery, spinal cord injury, Injury Severity Score (ISS), Trauma Injury Severity Score (TRISS), major venous injury, femoral venous catheters, and fractures of the pelvis, femur, or tibia.28 These findings have encouraged the early use of anticoagulated prophylaxis and/or optional inferior vena cava filters. BULGER ET AL
Fig 1. Annual incidence of VTE among residents of Worcester MA 1986, by age and sex. (Reproduced by permission from Anderson FA and co-workers. Arch Intern Med 151:933938, 1991. Copyright © 1991, American Medical Association. All rights reserved.)
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presentation in another 5% to 11% of patients.9 The most commonly associated malignancies included lung 25.6%, pancreas 17.4%, stomach 16.8%, and colon 15.2%.24,35,36
Oral Contraceptives and Hormone Replacement Therapy Epidemiologic studies have clearly established an association between oral contraceptives and VTE. Pharmacologic doses of estrogen are associated with increased factor VIIa levels as well as depressed antithrombin and protein S activity. The thrombotic risk is dependent on the estrogen dose, with preparations containing more than 50 g of estrogen being associated with the highest risk. The overall relative risk of VTE is 2.9, corresponding to a calculated absolute risk of approximately 3.3 per 10,000 users.38 Postmenopausal estrogen replacement dose is approximately onesixth those in oral contraceptives, however, recent data supports a small thromboembolic risk at these doses as well.9,39
Pregnancy and Postpartum The increased thrombotic risk associated with pregnancy has been attributed to an acquired prethrombotic state in combination with impaired venous outflow because of venous compression. Population based studies using Doppler ultrasound suggest an incidence of 0.75 per 1,000 deliveries.40 The risk of postpartum DVT is thought to be two- to three-folds higher than that during pregnancy.9
Hypercoagulable States The primary hypercoagulable states constitute those thrombophilic conditions that have a genetic basis and includes protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance or Factor V Leiden mutation, prothrombin mutation, hyperhomocysteinemia, and elevated Factor VIII levels. Protein C and S Deficiency: though recognized early, and discussed frequently, as responsible for hypercoagulable states, they are relatively rare disorders, found in only 0.2% of the population.41 Protein C and S are responsible for cleaving factors Va and VIIIa. Protein S is a vitamin K dependant cofactor that activates protein C. Protein C deficiency has demonstrated an 8 to 10 times increase in risk for VTE.42 Deficiencies of the naturally occurring anticoagulants antithrombin III, protein C, and protein S are present in only 5% to 10% of DVT patients.9 However, Protein S deficiency independent of Protein C deficiency has not demonstrated conclusive increased risk.43 Antithrombin III Deficiency: is present in 0.5% of the general population and results in increased circulating levels of thrombin and Factor Xa because of diminished inhibition. Patients with this disease present earlier with VTE, even as young as 25 years of age. Factor V Leiden Mutation: results from a point mutation in the factor V gene rendering it less sensitive to degradation by activated protein C. It is present in approximately 20% of DVT patients.9 It is an inherited disease and the relative risk for homozygotes of deep venous thrombosis is 80 times greater than the general population. It is also common, being found in 11% to 21% of patients with venous thromboemboli.42 Prothrombin Mutation: is a mutation of the prothrombin gene, resulting in increased plasma levels of prothrombin. It is
52
present in approximately 6% of those with venous thrombosis.9 Patients with a prothrombin mutation and Factor V Leiden mutation have an added risk for VTE. Hyperhomocysteinemia: is associated with venous thromboembolism and affects clotting through increases in platelet adhesiveness, increases in arachadonic acid metabolites, or by direct effects on the endothelium.42 The phenotypic expression of this abnormality varies both within and between families, although the risk is higher and the age at first thrombosis earlier among those with a family history of thrombosis. Elevated Factor VIII: patients with elevated factor VIII are at a six-fold increase in risk for VTE when compared with those with normal levels44 This condition is found in 11% of the population and is prevalent in 25% of patients with DVT. Von Villebrand factor, which carries factor VIII, has not been associated independently with an elevated risk for VTE.
Anticardiolipin and Lupus Anticoagulant Both are found individually and together as part of the antiphospholipid syndrome. This syndrome is associated with arterial and venous thrombosis and fetal loss in pregnant patients. The secondary form of the disease is associated with autoimmune conditions such as lupus. Anticardiolipin antibody and lupus anticoagulant were associated with a two-fold and six-fold respective increase in risk for VTE.45
Prior Venous Thromboembolism As many as 26% of cases will have a previous history of DVT.9 The incidence of recurrent DVT is higher among those with irreversible thrombotic risk factors and those with idiopathic DVT.
Other Risk Factors Although lacking the strong epidemiologic support central venous instrumentation, antiphospholipid antibodies, and inflammatory bowel disease have been associated to have an increased risk for DVT.9 Obesity, varicose veins, myocardial infarction, and congestive heart failure have not consistently been identified as independent risk factors for acute DVT.23
Major Complications of Acute DVT The major complications of DVT are death, pulmonary embolism, phlegmasia cerulea dolens, and the postthrombotic syndrome (PTS).
Mortality Many investigators have noted that mortality after an episode of acute DVT exceeds that expected in an age matched population. Excess mortality is likely a result of the frequency of comorbid medical conditions. Although the in hospital case-fatality rate for DVT is only 5%, 3 and 5 year mortality rates of 30% and 39%, respectively, have been noted.2,46
Pulmonary Embolism Symptomatic pulmonary embolism (PE) is the most important acute complication of DVT, accompanying the presentation in approximately 10% of cases.47 In general, clinical studies of VTE (DVT and PE) that do not include autopsy data report an incidence of clinically diagnosed DVT to be about twice that of EPIDEMIOLOGY OF DVT
pulmonary embolism, whereas, those including both clinical and autopsy data report a higher proportion of pulmonary embolism than DVT.13 Most PE are clinically silent and symptoms correlate poorly with the presence or absence of perfusion defects on lung scan.47 The high incidence of silent PE has led to the concept of DVT and PE being a “pathophysiologic continuum.”48 The incidence of symptomatic PE in the U.S. has been estimated to be 630,000 cases per year.49 Approximately 90% of PE arise from the lower extremity veins.30,50 Venous thromboemboli in a retrospective review by Ouriel, were noted to occur 83% in the calf, 53% in the femoral popliteal vein, and 9% involved the iliac veins.51 The peroneal vein and the left side veins were noted to be involved with greater frequency attributed to iliac vein webs. In addition, the same study noted that postoperative venous thromboemboli were more likely to be distal, while proximal and right-sided VTE occurred more frequently in patients with malignancy. With appropriate treatment, the rate of recurrent nonfatal and fatal venous thromboembolism has been reported to be 3.8% and 0.5%, respectively.52 It is estimated that PE is the third most frequent cause of death in the U.S., accounting for approximately 200,000 deaths per year.50
Phlegmasia Cerulea Dolens Phlegmasia cerulea dolens is rare, developing in 1% of patients with iliofemoral DVT.53 It is characterized by massive extremity swelling, cyanosis, and pain. On physical examination the extremity is often cold with absent arterial pulses. Cyanosis is a result of extravasation of red blood cells into the interstitium. The increased interstitial tissue pressure caused by edema leads to arrest of capillary blood flow, tissue ischemia and ultimately gangrene. Mortality has been reported in 25% of cases and amputation in 12% to 25% of survivors.54-56
PTS The major chronic complication of acute DVT is the PTS.57 PTS is a result of valvular incompetence and residual obstruction after venous thrombosis. The remaining thrombus not only damages the valves permanently precipitating reflux, but the thrombus also prevents adequate venous return from the extremity. The single most important implicated cause of PTS is valvular insufficiency in the popliteal and superficial femoral veins.58-60 The chronic elevation of venous pressures (venous hypertension) in the lower limb result is an extremity that is swollen, painful, heavy, and worsened by standing. The patient may present with muscle fatigue (venous claudication). The long term changes associated with this syndrome include hyperpigmentation from hemosiderin deposition, ulcerations, and lipodermatosclerosis or subcutaneous atrophy.61 The incidence of post thrombotic syndrome after DVT was from 17% at 1 year to 29% at 8 years follow-up, with half of the patients resolving their symptoms during that time.62 Symptoms may be improved with compressive stockings applied daily, and thrombolysis in the acute phase of DVT.63 PTS becomes apparent only months to years after an episode of DVT. When followed for 10 years, over 60% to 80% of patients with a past diagnosis of DVT had post thrombotic ankle ulceration or symptoms of chronic edema and pain.57,64-67 Iliofemoral DVT accounts for 20% of all DVT, with 66% developing PTS and 10% to 15% developing venous stasis skin ulcers.57,68-70 BULGER ET AL
Summary Clinical features of acute DVT include unilateral leg swelling with dependent edema, localized pain and tenderness, skin warm to touch, erythematous skin, and dyspnea, chest pain, or hemoptysis. Homan’s sign does not help diagnose or exclude DVT. DVT cannot be safely diagnosed or excluded on history and physical examination alone. Imaging studies are necessary. Because of the silent nature of this disease and the low rate of autopsies performed in the U.S., the true incidence, prevalence, and mortality rates remain elusive. Venous thrombosis results from an imbalance between the fibrinolytic and coagulation cascades. Many causes or risk factors for increased coagulation and deep vein thrombosis have been identified. These risk factors fundamentally promote stasis, result in damaged intima, or intrinsically have elevated levels of the components necessary for the coagulation process. Greatest risk elevation occurs when these factors are applied in combination. Identifying these risk factors in a given patient population allows early prophylaxis to be instituted and morbidity to be decreased. Lastly, DVT and PE should be considered as a “pathophysiologic continuum.”
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42. Rosendaal FR: Risk factors for venous thrombosis: Prevalence, risk, and interaction. Semim Hematol 34:17, 1997 43. Kim V, Spandorfer MD: Epidemiology of Venous Thromboembolic Disease. Emerg Med Clin North Am 19:4, 2001 44. Dalen JE: Pulmonary embolism: What have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest 122:4, 2002 45. Wahl DG: Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus-a meta-analysis. Lupus 6:467-473, 1997 46. Beyth RJ, Cohen AM, Landefeld CS: Long-term outcome of deepvein thrombosis. Arch Intern Med 155:1031-1037, 1995 47. Plate G, Ohlin P, Eklof B: Pulmonary embolism in acute ileofemoral venous thrombosis. Br J Surg 72:912-915, 1985 48. Huisman MV, Buller HR, ten Cate JW, et al: Unexpected high prevalence of silent pulmonary embolism in patients with deep venous thrombosis. Chest 95:498-502, 1989 49. Dalen JE, Alpert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17:259-270, 1975 50. Girolami A, Prandoni P, Simioni P, et al: The pathogenesis of venous thromboembolism. Haematologica 80:25-35, 1995 (suppl) 51. Ouriel K, Green RM, Greenberg RK: The anatomy of deep venous thrombosis of the lower extremity. J Vasc Surg 31:895-900, 2000 52. Douketis JD, Kearon C, Bates S, et al: Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 279:458-462, 1998 53. Eidt JF, Solis MM, Thompson BW: Venous thrombectomy in management of deep venous thrombosis, in Strandness DE Jr, Van Breda A (eds): Vascular Diseases: Surgical and Interventional Therapy. New York, Elsevier, 1994, pp 905-912 54. Weaver FA, Mecham PW, Adkins RB, et al: Phlegmasia cerulean dolens: Therapeutic considerations. South Med J 81:306-312, 1988 55. Hood DB, Weaver FA, Modrall JG, et al: Advances in the treatment of phlegmasia cerulean dolens. Am J Surg 166:206-210, 1993 56. Perkins JM, Magee TR, Galland RB: Phlegmasia caerulea dolens and gangrene. Br J Surg 83:19-23, 1996 57. Strandness DE, Langlois Y, Cramer M, et al: Long-term sequela of acute venous thrombosis. JAMA 250:1289-1292, 1983 58. Shull KC, Nicolaides AN, Fernandes e Fernandes J, et al: Significance of popliteal reflux in relation to ambulatory venous pressure and ulceration. Arch Surg 114:1304-1306, 1979 59. Markel A, Manzo RA, Bergelin RO, et al: Valvular reflux after deep vein thrombosis: Incidence and time of occurrence. J Vasc Surg 15:377-384, 1992 60. Meissner MH, Manzo RA, Bergelin RO, et al: Deep venous insufficiency: The relationship between lysis and subsequent reflux. J Vasc Surg 18:596-608, 1993 61. Kearon C: Natural history of venous thromboembolism. Circulation 107:I22-I30, 2003 (suppl 1) 62. Prandoni P, Lensing AWA, Cogo A, et al: The long term clinical course of acute deep venous thrombosis. Ann Intern Med 125:1-7, 1996 63. Turpie AGG, Levine MN, Hirsh J, et al: Tissue plasminogen activatorvs heparin in deep vein thrombosis. Chest 97:172s-175s, 1990 64. Killewich LA, Bedford GR, Beach KW, Strandness DE: Spontaneous lysis of deep venous thrombi: Rate and outcome. J Vasc Surg 9:89-97, 1989 65. Killewich LA, Martin R, Cramer M, et al: An objective assessment of the physiological changes in the postthrombotic syndrome. Arch Surg 120:424-426, 1985 66. Johnson BF, Manza RA, Bergelin RO, et al: Relationship between changes in the deep venous system and the development of the post-thrombotic syndrome after an acute episode of lower limb deep vein thrombosis: A one to six year follow-up. J Vasc Surg 21:307312, 1995 67. Akesson H, Brudin L, Dahlstrom JA, et al: Venous function assessed during a five year period after acute iliofemoral venous thrombosis treated with anticoagulation. Eur J Vasc Surg 4:43-48, 1990 68. Bauer G: The etiology of leg ulcers and their treatment by resection of the popliteal vein. J Int Chir 8:937-967, 1948 69. Lindner DJ, Edwards JM, Phinney ES, et al: Long-term hemodynamic and clinical sequelae of lower extremity deep vein thrombosis. J Vasc Surg 4:436-442, 1986 70. O’Donnell TF Jr, Browse NL, Burnand KG, et al: The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res 22:483-488, 1977
EPIDEMIOLOGY OF DVT
Although the factors leading to venous thrombosis have been known for over a century, Virchow’s initial model of thrombosis has been extensively refined. Activated coagulation is now recognized to be of primary importance in venous thrombogenesis; the concept of venous injury has been expanded to include molecular changes in the endothelium; and stasis has been redefined as a largely permissive factor. Furthermore, it is now clear that venous thrombi undergo a dynamic evolution beginning early after their formation. The natural history of acute deep venous thrombosis (DVT) is a balance between recurrent thrombotic events and processes that restore the venous lumen, both of which have important implications for the development of complications. Although pulmonary embolism (PE) is clearly the most life threatening complication of acute DVT, the long term socio-economic consequences of the post thrombotic syndrome (PTS) have perhaps been underemphasized in clinical trials. The development of post-thrombotic manifestations is related to both residual venous obstruction and valvular incompetence. Recognition of the factors contributing to a poor outcome, including recurrent thrombotic events, the rate of recanalization, the global extent of venous reflux, and the anatomic distribution of reflux and obstruction is important, as there may be therapeutic alternatives to alter the natural history of acute DVT. The treatment alternatives will continue to expand with the introduction of new therapeutic drugs, for both systemic and catheter-directed therapy, and mechanical thrombectomy devices. The primary care physician is challenged with the task of correctly evaluating deep vein thrombosis and providing his patient with access to the most clinically appropriate, and cost-effective, diagnostic and management options available. This article will review the epidemiology of DVT, its risk factors and major complications. © 2004 Elsevier Inc. All rights reserved.
here are several U.S. studies that have examined the epidemiology of acute deep venous thrombosis (DVT). In the Tecumseh Community Health Study, a study on healthy volunteers, Coon found an annual DVT incidence of 122 per 100,000.1 Anderson performed a community-wide study in 16 short-stay hospitals in Worcester, Mass over 1 year and found an average annual incidence of 48 per 100,000.2 Silverstein performed a population based study in Olmstead County, MN, from 1966 to 1990 and found an overall average incidence of acute DVT in 48 per 100,000 per year.3 Kniffin reviewed Medicare claims from 1986 to 1989 and found an annual incidence of acute DVT of 1.8 per 1000 in the age group of 65 to 69 years old.4 White studied the California Patient Discharge Data Set
T
From the Section of Interventional Radiology, Department of Diagnostic Radiology and Nuclear Medicine, and Section of Vascular Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL. Address reprint requests to Nilesh H. Patel, MD, Affiliated Radiologists, SC, 1725 West Harrison Street, Suite 456, Chicago, IL 60612. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0002$30.00/0 doi:10.1053/j.tvir.2004.02.001
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from 1991 to 1994 and found an annual incidence of acute DVT of 230 per 1000,000 in Caucasians above the age of 18.5 The estimated incidence of clinically recognized acute DVT in the US is about 116,000 to over 250,000 new cases per year.1,2
Risk Factors As initially described by Virchow, three factors are of primary importance in the development of venous thrombosis: (1) abnormalities of blood flow, (2) abnormalities of blood, and (3) vessel wall injury.8 Recent advances in coagulation and vascular biology have redefined the importance of Virchow’s model. Not all components of Virchow’s triad are of equal importance in all patients. Several of the currently identified risk factors for acute DVT can be related to one or more of these elements (Table 1). The risk of DVT increases with age, with a relative risk of 1.9 per 10 year increase.9 Other factors that increase DVT risk include trauma (13-fold), surgery (6- to 22-fold), malignancy (5-fold), oral contraceptive use (2- to 4-fold), and lupus anticoagulant (6-fold).9-13 It is now recognized that DVT arise from the interaction of multiple inherited and acquired risk factors. Rosendaal promoted that this complex interaction be referred to as “thrombotic potential.”14 When the cumulative thrombotic potential of all risk factors exceeds a certain threshold, clinical thrombosis is likely. This theory is supported by the observation that the risk of DVT increases with the number of risk factors present.2,15 The general population of hospitalized patients has an average of 1.5 risk factors per patient, with 26% having three or more risk factors.9,16 Three or more risk factors are present in 30% of out-patients with DVT.2,9,15 In symptomatic outpatients, the odds ratio for DVT increases from 1.26 for one risk factor to 3.88 for three or more risk factors.9,15 These risk factors may act synergistically to increase the risk of DVT dramatically above the sum of the individual factors. The thromboembolic risk of surgery has been estimated to be 1.6%, and the risk associated with antithrombin deficiency to be 0.8% per year, respectively. The thromboembolic risk of patients with both risk factors (surgery, antithrombin deficiency) has been estimated to be 12.7% per year.17 Likewise, the use of third generation oral contraceptives may act synergistically with the Factor V Leiden mutation, increasing thromboembolic risk 30- to 50-fold.18-20
Age, Gender, and Race DVT is rare in children but exponentially increases in incidence between the age of 20 and 80 years (Fig 1).2 Kniffin found the annual rate of DVT increased from 1.8 per 1000 at age 65 to 69 years to 3.1 by age 85 to 99 years.4 The increase in calculated cumulative probability of venous thromboembolism (VTE) approaches 10.7% by age 80.11,21,22 The increase risk of DVT with
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 50-54
Surgery
TABLE 1. Risk Factors for Acute DVT Risk Factor
Hypercoagulability
Stasis
Venous Injury
Age Immobilization Surgery Trauma Malignancy Primary Hypercoagulable States (antithrombin III deficiency, Protein C and Protein S deficiency, Factor V Leiden, Prothrombin 20210A, Increase Factor VIII, Hyperhomocysteinemia) History of DVT Family History Oral Contraceptives Estrogen Replacement Pregnancy and Puerperium Antiphospholipid Antibodies (lupus anticoagulant and anticardiolipin antibody) Central Venous Catheters Inflammatory Bowel Disease Obesity Myocardial Infarction/CHF Varicose Veins
X
X X X X
X
X X X X
X X X X X X
Patients undergoing surgery are subject to a 6- to 22-fold increase in risk for DVT. Abdominal, pelvic, orthopedic, neurosurgical, and oncologic surgeries place patients at the highest risk because of immobilization, secondary venous stenosis, and endothelial damage.17 Of note, type of anesthesia has not been identified as an independent risk factor for DVT.29 In addition to immobilization, stasis, and endothelial damage promoting DVT, surgery has been associated with activated coagulation and transient depression of fibrinolysis. An increase in thrombin activation as well as elevated levels of plasminogen activator inhibitor-1 (PAI-1) during the perioperative period have been described.30
Immobilization X
X X X X X
advanced age is likely related to multiple age associated factors including an increased number of major thrombotic risk factors, an acquired prothrombotic state as suggested by increased levels of thrombin activation markers, and changes in the venous system associated with increased stasis.23 Silverstein reported minor gender differences in a large population DVT study, with 50 DVT per 100,000 women and 47 DVT per 100,000 men.3 Furthermore, they noted that the incidence was somewhat higher among women of childbearing age, however, in older age groups the incidence was generally higher among men. Some have not found a significant difference in the incidence of DVT between men and women, while others have noted a slightly increased risk in males (relative risk 1.4).2,15,24 In a California study by White, the annual incidence of DVT per 100,000 was 23 in Caucasians, 29.3 in African Americans, 13.9 in Hispanics, and 6 in Asians and Pacific Islanders.5 Others have found no differences in the incidence of DVT between African Americans and Caucasians.4,25 Racial and ethnic differences in genetic risk factors, including blood group and the factor V Leiden mutation, do exist and may account for the differences in rates of DVT.5,26,27
Before the use of DVT prophylaxis, the autopsy incidence of lower extremity thrombosis was noted to increase within 3 days of bedrest. This rose rapidly to 15% at 1 week, 77% at 2 weeks and 94% at 4 weeks of confinement.31 The importance of immobilization is further emphasized by the observations that thrombosis following bedrest is frequently bilateral while that associated with stroke is often confined to the paralyzed limb. The relationship between DVT and prolonged travel has been controversial; however, there is one case control study that showed an association between DVT and travel of greater than 4 hours duration.32
Malignancy Malignancy increases the risk of DVT by direct tumor compression of the veins, invasion of the vessels causing endothelial damage, and increased secretion of procoagulant factor VIII and fibrinogen.33,34 DVT may complicate 19% to 30% of malignancies with idiopathic thrombosis present in 3% to 23% of patients a the time of diagnosis or may develop 1 to 2 years after
Trauma Trauma patients are subject to a 13-fold increase in risk for DVT. This risk can be attributed to release of vasoactive amines and intimal injury. Unfortunately, the risk from the trauma is compounded by the fact that many of these patients have neurologic and orthopedic injuries resulting in prolonged immobility and venous stasis, which will impart additional risk. Factors identified as important determinants of DVT in this population have included advanced age, blood transfusion, surgery, spinal cord injury, Injury Severity Score (ISS), Trauma Injury Severity Score (TRISS), major venous injury, femoral venous catheters, and fractures of the pelvis, femur, or tibia.28 These findings have encouraged the early use of anticoagulated prophylaxis and/or optional inferior vena cava filters. BULGER ET AL
Fig 1. Annual incidence of VTE among residents of Worcester MA 1986, by age and sex. (Reproduced by permission from Anderson FA and co-workers. Arch Intern Med 151:933938, 1991. Copyright © 1991, American Medical Association. All rights reserved.)
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presentation in another 5% to 11% of patients.9 The most commonly associated malignancies included lung 25.6%, pancreas 17.4%, stomach 16.8%, and colon 15.2%.24,35,36
Oral Contraceptives and Hormone Replacement Therapy Epidemiologic studies have clearly established an association between oral contraceptives and VTE. Pharmacologic doses of estrogen are associated with increased factor VIIa levels as well as depressed antithrombin and protein S activity. The thrombotic risk is dependent on the estrogen dose, with preparations containing more than 50 g of estrogen being associated with the highest risk. The overall relative risk of VTE is 2.9, corresponding to a calculated absolute risk of approximately 3.3 per 10,000 users.38 Postmenopausal estrogen replacement dose is approximately onesixth those in oral contraceptives, however, recent data supports a small thromboembolic risk at these doses as well.9,39
Pregnancy and Postpartum The increased thrombotic risk associated with pregnancy has been attributed to an acquired prethrombotic state in combination with impaired venous outflow because of venous compression. Population based studies using Doppler ultrasound suggest an incidence of 0.75 per 1,000 deliveries.40 The risk of postpartum DVT is thought to be two- to three-folds higher than that during pregnancy.9
Hypercoagulable States The primary hypercoagulable states constitute those thrombophilic conditions that have a genetic basis and includes protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance or Factor V Leiden mutation, prothrombin mutation, hyperhomocysteinemia, and elevated Factor VIII levels. Protein C and S Deficiency: though recognized early, and discussed frequently, as responsible for hypercoagulable states, they are relatively rare disorders, found in only 0.2% of the population.41 Protein C and S are responsible for cleaving factors Va and VIIIa. Protein S is a vitamin K dependant cofactor that activates protein C. Protein C deficiency has demonstrated an 8 to 10 times increase in risk for VTE.42 Deficiencies of the naturally occurring anticoagulants antithrombin III, protein C, and protein S are present in only 5% to 10% of DVT patients.9 However, Protein S deficiency independent of Protein C deficiency has not demonstrated conclusive increased risk.43 Antithrombin III Deficiency: is present in 0.5% of the general population and results in increased circulating levels of thrombin and Factor Xa because of diminished inhibition. Patients with this disease present earlier with VTE, even as young as 25 years of age. Factor V Leiden Mutation: results from a point mutation in the factor V gene rendering it less sensitive to degradation by activated protein C. It is present in approximately 20% of DVT patients.9 It is an inherited disease and the relative risk for homozygotes of deep venous thrombosis is 80 times greater than the general population. It is also common, being found in 11% to 21% of patients with venous thromboemboli.42 Prothrombin Mutation: is a mutation of the prothrombin gene, resulting in increased plasma levels of prothrombin. It is
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present in approximately 6% of those with venous thrombosis.9 Patients with a prothrombin mutation and Factor V Leiden mutation have an added risk for VTE. Hyperhomocysteinemia: is associated with venous thromboembolism and affects clotting through increases in platelet adhesiveness, increases in arachadonic acid metabolites, or by direct effects on the endothelium.42 The phenotypic expression of this abnormality varies both within and between families, although the risk is higher and the age at first thrombosis earlier among those with a family history of thrombosis. Elevated Factor VIII: patients with elevated factor VIII are at a six-fold increase in risk for VTE when compared with those with normal levels44 This condition is found in 11% of the population and is prevalent in 25% of patients with DVT. Von Villebrand factor, which carries factor VIII, has not been associated independently with an elevated risk for VTE.
Anticardiolipin and Lupus Anticoagulant Both are found individually and together as part of the antiphospholipid syndrome. This syndrome is associated with arterial and venous thrombosis and fetal loss in pregnant patients. The secondary form of the disease is associated with autoimmune conditions such as lupus. Anticardiolipin antibody and lupus anticoagulant were associated with a two-fold and six-fold respective increase in risk for VTE.45
Prior Venous Thromboembolism As many as 26% of cases will have a previous history of DVT.9 The incidence of recurrent DVT is higher among those with irreversible thrombotic risk factors and those with idiopathic DVT.
Other Risk Factors Although lacking the strong epidemiologic support central venous instrumentation, antiphospholipid antibodies, and inflammatory bowel disease have been associated to have an increased risk for DVT.9 Obesity, varicose veins, myocardial infarction, and congestive heart failure have not consistently been identified as independent risk factors for acute DVT.23
Major Complications of Acute DVT The major complications of DVT are death, pulmonary embolism, phlegmasia cerulea dolens, and the postthrombotic syndrome (PTS).
Mortality Many investigators have noted that mortality after an episode of acute DVT exceeds that expected in an age matched population. Excess mortality is likely a result of the frequency of comorbid medical conditions. Although the in hospital case-fatality rate for DVT is only 5%, 3 and 5 year mortality rates of 30% and 39%, respectively, have been noted.2,46
Pulmonary Embolism Symptomatic pulmonary embolism (PE) is the most important acute complication of DVT, accompanying the presentation in approximately 10% of cases.47 In general, clinical studies of VTE (DVT and PE) that do not include autopsy data report an incidence of clinically diagnosed DVT to be about twice that of EPIDEMIOLOGY OF DVT
pulmonary embolism, whereas, those including both clinical and autopsy data report a higher proportion of pulmonary embolism than DVT.13 Most PE are clinically silent and symptoms correlate poorly with the presence or absence of perfusion defects on lung scan.47 The high incidence of silent PE has led to the concept of DVT and PE being a “pathophysiologic continuum.”48 The incidence of symptomatic PE in the U.S. has been estimated to be 630,000 cases per year.49 Approximately 90% of PE arise from the lower extremity veins.30,50 Venous thromboemboli in a retrospective review by Ouriel, were noted to occur 83% in the calf, 53% in the femoral popliteal vein, and 9% involved the iliac veins.51 The peroneal vein and the left side veins were noted to be involved with greater frequency attributed to iliac vein webs. In addition, the same study noted that postoperative venous thromboemboli were more likely to be distal, while proximal and right-sided VTE occurred more frequently in patients with malignancy. With appropriate treatment, the rate of recurrent nonfatal and fatal venous thromboembolism has been reported to be 3.8% and 0.5%, respectively.52 It is estimated that PE is the third most frequent cause of death in the U.S., accounting for approximately 200,000 deaths per year.50
Phlegmasia Cerulea Dolens Phlegmasia cerulea dolens is rare, developing in 1% of patients with iliofemoral DVT.53 It is characterized by massive extremity swelling, cyanosis, and pain. On physical examination the extremity is often cold with absent arterial pulses. Cyanosis is a result of extravasation of red blood cells into the interstitium. The increased interstitial tissue pressure caused by edema leads to arrest of capillary blood flow, tissue ischemia and ultimately gangrene. Mortality has been reported in 25% of cases and amputation in 12% to 25% of survivors.54-56
PTS The major chronic complication of acute DVT is the PTS.57 PTS is a result of valvular incompetence and residual obstruction after venous thrombosis. The remaining thrombus not only damages the valves permanently precipitating reflux, but the thrombus also prevents adequate venous return from the extremity. The single most important implicated cause of PTS is valvular insufficiency in the popliteal and superficial femoral veins.58-60 The chronic elevation of venous pressures (venous hypertension) in the lower limb result is an extremity that is swollen, painful, heavy, and worsened by standing. The patient may present with muscle fatigue (venous claudication). The long term changes associated with this syndrome include hyperpigmentation from hemosiderin deposition, ulcerations, and lipodermatosclerosis or subcutaneous atrophy.61 The incidence of post thrombotic syndrome after DVT was from 17% at 1 year to 29% at 8 years follow-up, with half of the patients resolving their symptoms during that time.62 Symptoms may be improved with compressive stockings applied daily, and thrombolysis in the acute phase of DVT.63 PTS becomes apparent only months to years after an episode of DVT. When followed for 10 years, over 60% to 80% of patients with a past diagnosis of DVT had post thrombotic ankle ulceration or symptoms of chronic edema and pain.57,64-67 Iliofemoral DVT accounts for 20% of all DVT, with 66% developing PTS and 10% to 15% developing venous stasis skin ulcers.57,68-70 BULGER ET AL
Summary Clinical features of acute DVT include unilateral leg swelling with dependent edema, localized pain and tenderness, skin warm to touch, erythematous skin, and dyspnea, chest pain, or hemoptysis. Homan’s sign does not help diagnose or exclude DVT. DVT cannot be safely diagnosed or excluded on history and physical examination alone. Imaging studies are necessary. Because of the silent nature of this disease and the low rate of autopsies performed in the U.S., the true incidence, prevalence, and mortality rates remain elusive. Venous thrombosis results from an imbalance between the fibrinolytic and coagulation cascades. Many causes or risk factors for increased coagulation and deep vein thrombosis have been identified. These risk factors fundamentally promote stasis, result in damaged intima, or intrinsically have elevated levels of the components necessary for the coagulation process. Greatest risk elevation occurs when these factors are applied in combination. Identifying these risk factors in a given patient population allows early prophylaxis to be instituted and morbidity to be decreased. Lastly, DVT and PE should be considered as a “pathophysiologic continuum.”
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EPIDEMIOLOGY OF DVT