**1. Introduction**

Deep vein thrombosis is a clinical challenge for doctors of all disciplines. It can complicate the course of a disease but might also be encountered in the absence of precipitating disorders. Thrombosis can take place in any section of the venous system, but arises most frequently in the deep veins of the leg. Long-term morbidity due to post-thrombotic syndrome is common and can be substantial. The major concern, however, is embolisation of the thrombus to the lung, which can be fatal. Deep vein thrombosis is highly prevalent and poses a burden on health economy. The disorder and its sequelae are also among the best examples of preventable diseases. Relevant data for the frequency of deep vein thrombosis derive from large community-based studies because they mainly reflect symptomatic rather than asymptomatic disease. In a systematic review, the incidence of first deep vein thrombosis in the general population was 0·5 per 1000 person-years.1 The disorder is rare in children younger than 15 years,2,3 but its frequency increases with age, with incidence per 1000 person-years of 1·8 at age 65–69 years and 3·1 at age 85–89 years.4 Two-thirds of first-time episodes of deep vein thrombosis are caused by risk factors, including surgery, cancer, immobilisation, or admission for other reasons.5,6 Risk for first deep vein thrombosis seems to be slightly higher in men than in women.6,9 In a populationbased cohort study, the age-adjusted incidence of first venous thromboembolism was 1·3 per 1000 person-years in men and 1·1 per 1000 person-years in women.2 It is noteworthy that the risk for recurrence of this disorder is higher in men than in women.6,10


Risk Factors of Deep Vein Thrombosis 3

increased from 2.6 to 2.9 mm (IQR, 2.3– 4.0 mm) in the control group.13 Comerota et al14 found that in patients undergoing total hip replacement surgery, handling of soft tissue (muscle) during surgery leads to venodilation, whereas bone manipulation leads to venoconstriction. The venous dilatation that occurs during surgery causes cracks in the endothelium, which provides a nidus for thrombosis as the blood coagulation system is activated. The researchers also showed that pharmacologic control of venodilation during surgery reduced postoperative DVT.14 Microscopic vessel wall damage, 15 such as that demonstrated in patients undergoing hip and knee replacement surgeries, also contributes to the development of VTE. 16,17 Tissue factor released from the blood vessel wall after injury drives thrombus formation,18 which may help explain the increased risk of VTE in patients undergoing surgery. The third factor in Virchow's triad, hypercoagulability, is linked to a number of factors, including certain genetic traits. Deficiencies of antithrombin, protein C, or protein S, or mutations of factor V Leiden or factor II (prothrombin) G20210A genes lead to hypercoagulable states.11 Although these genetic factors account for only a small percentage of the total cases of VTE, more than half of all patients with juvenile or idiopathic VTE have been identified with an inherited thrombophilic condition.11. Given that VTE is the leading preventable cause of in-hospital deaths,19 every patient should be screened before other lesser screens are performed (bedsores, risk of falls, nutritional evaluation, and so forth). Stated another way— every patient deserves a proper history and

physical to uncover any possible factors that might increase their risk of a VTE.

Low risk (minor surgery in patients < 40 years

Moderate risk (minor surgery and additional

High risk (surgery in patients > 60 years or age 40-60 years with additional risk factors (previous venous thromboembolism, cancer, thrombophilia)

Highest risk (surgery in patients with multiple risk factors [age > 40 years, cancer, previous venous thromboembolism]: hip or knee

arthroplasty, hip fracture surgery; major trauma –

spinal cord surgery)

Calf Proximal Clinical Fatal

with no additional risk factors) 2% 0-4% 0-2% <0,01%

risk factor 10-20% 2-4% 1-2% 0,1-0,4%

Modified from reference 16 with permission of the American College of Chest Physicians.

In 1992, the Thromboembolic Risk Factors (THRIFT) Consensus Group identified acquired risk factors for VTE.20 Sixteen years later, the most recent update of the American College of Chest Physicians (ACCP) guidelines for VTE prophylaxis reveals essentially the same risk factors for VTE as those identified by THRIFT, with the addition of a few new ones, including acute medical illness, and the removal of smoking as a separate risk factor (Table

Table 1. Risk of venous thromboembolism in surgical patients without prophylaxis

**Deep vein thrombosis** 

20-40% 4-8% 2-4% 0,4-1,0%

40-80% 10-20% 4-10% 0,2-5%

**Pulmonary embolism** 


Rudolph Virchow is recognized as the first person to link the development of VTE to the presence of at least 1 of 3 conditions: venous stasis, vascular injury, and/or hypercoagulability. 11 Each of these factors can alter the delicate hemostatic balance toward hypercoagulability and development of thrombosis. Several aspects of surgery can be linked to Virchow's triad. Coleridge-Smith et al12 reported in 1990 that venous stasis occurs during general surgery, with veins dilating 22% to 28% in patients undergoing general anesthesia and surgery and up to 57% in those who also received an infusion of 1 L of saline during surgery. The investigators suggested that it is this intraoperative venous distension that underlies the risk for DVT in patients undergoing surgery. They suggested that the venous distension is the result of loss of muscle tone that is caused by the muscle relaxants used during surgery. Muscle paralysis resulting from regional anesthesia also can lead to venous dilatation. These effects can be modified to some extent by the use of graduated compression stockings during surgery.13 In a study of 40 patients undergoing surgery of the abdomen or neck, the median vein diameter in the extremity studied was 2.6 mm at the beginning of surgery in both the control and intervention groups (control group, n = 20; median vein diameter, 2.6 mm; interquartile range [IQR], 2.1–3.3 mm; stocking group, n =20; median vein diameter, 2.6 mm; IQR, 2.1–3.7 mm). This decreased to a median vein diameter of 1.6 mm (IQR, 1.3–2.8 mm) after application of a stocking, whereas vein diameter

Rudolph Virchow is recognized as the first person to link the development of VTE to the presence of at least 1 of 3 conditions: venous stasis, vascular injury, and/or hypercoagulability. 11 Each of these factors can alter the delicate hemostatic balance toward hypercoagulability and development of thrombosis. Several aspects of surgery can be linked to Virchow's triad. Coleridge-Smith et al12 reported in 1990 that venous stasis occurs during general surgery, with veins dilating 22% to 28% in patients undergoing general anesthesia and surgery and up to 57% in those who also received an infusion of 1 L of saline during surgery. The investigators suggested that it is this intraoperative venous distension that underlies the risk for DVT in patients undergoing surgery. They suggested that the venous distension is the result of loss of muscle tone that is caused by the muscle relaxants used during surgery. Muscle paralysis resulting from regional anesthesia also can lead to venous dilatation. These effects can be modified to some extent by the use of graduated compression stockings during surgery.13 In a study of 40 patients undergoing surgery of the abdomen or neck, the median vein diameter in the extremity studied was 2.6 mm at the beginning of surgery in both the control and intervention groups (control group, n = 20; median vein diameter, 2.6 mm; interquartile range [IQR], 2.1–3.3 mm; stocking group, n =20; median vein diameter, 2.6 mm; IQR, 2.1–3.7 mm). This decreased to a median vein diameter of 1.6 mm (IQR, 1.3–2.8 mm) after application of a stocking, whereas vein diameter

Antiphospholiped syndrome

Myeloproliferative diseases

Superficial vein thrombosis Congenital venous malformation

Paroxysmal nocturnal haemoglobinuria

Dyslipoproteinaemia Nephrotic syndrome

Behçet's syndrome Varicose veins

Long-distance travel Prolonged bed rest İmmobilisation Limb paresis

Chronic care facility stay Pregnancy/Puerperium Oral contraceptives

Chemotheraphy Tamoxifen Thalidomide Antipsychotics Central Venous catheter

İntravenous drug abuse

Other drugs

Vena cava filter

Hormone replacement theraphy Heparin-induced thrombocitopenia increased from 2.6 to 2.9 mm (IQR, 2.3– 4.0 mm) in the control group.13 Comerota et al14 found that in patients undergoing total hip replacement surgery, handling of soft tissue (muscle) during surgery leads to venodilation, whereas bone manipulation leads to venoconstriction. The venous dilatation that occurs during surgery causes cracks in the endothelium, which provides a nidus for thrombosis as the blood coagulation system is activated. The researchers also showed that pharmacologic control of venodilation during surgery reduced postoperative DVT.14 Microscopic vessel wall damage, 15 such as that demonstrated in patients undergoing hip and knee replacement surgeries, also contributes to the development of VTE. 16,17 Tissue factor released from the blood vessel wall after injury drives thrombus formation,18 which may help explain the increased risk of VTE in patients undergoing surgery. The third factor in Virchow's triad, hypercoagulability, is linked to a number of factors, including certain genetic traits. Deficiencies of antithrombin, protein C, or protein S, or mutations of factor V Leiden or factor II (prothrombin) G20210A genes lead to hypercoagulable states.11 Although these genetic factors account for only a small percentage of the total cases of VTE, more than half of all patients with juvenile or idiopathic VTE have been identified with an inherited thrombophilic condition.11. Given that VTE is the leading preventable cause of in-hospital deaths,19 every patient should be screened before other lesser screens are performed (bedsores, risk of falls, nutritional evaluation, and so forth). Stated another way— every patient deserves a proper history and physical to uncover any possible factors that might increase their risk of a VTE.


Table 1. Risk of venous thromboembolism in surgical patients without prophylaxis

In 1992, the Thromboembolic Risk Factors (THRIFT) Consensus Group identified acquired risk factors for VTE.20 Sixteen years later, the most recent update of the American College of Chest Physicians (ACCP) guidelines for VTE prophylaxis reveals essentially the same risk factors for VTE as those identified by THRIFT, with the addition of a few new ones, including acute medical illness, and the removal of smoking as a separate risk factor (Table

Risk Factors of Deep Vein Thrombosis 5

based on a quality-of-life decision rather than a critical medical need, the patient may come to a different decision about whether to proceed.30 A common misconception among physicians is that individual risk assessment takes longer and is more cumbersome than group risk assessment. However, individual assessment can be accomplished with, for example, a simple assessment form that merely captures information from the history and

Among all patients with PE in the PIOPED II trial 94% had 1 or more of the following assessed risk factors: bed rest within the last month of 3 days or more, travel within the last month of 4 hours or more, surgery within 3 months, malignancy, past history of DVT or PE, trauma of lower extremities or pelvis, central venous instrumentation within 3 months, stroke, paresis or paralysis, heart failure or chronic obstructive pulmonary disease (COPD).31 Immobilization of only 1 or 2 days may predispose to PE, and 65% of those who

Investigations that reported an increased risk for VTE caused by obesity have been criticized because they failed to control for hospital confinement or other risk factors.33 High proportions of patients with VTE have been found to be obese,13,34 but the importance of the association is diminished because of the high proportion of obesity in the general population.35 Some investigations showed an increased risk ratio for DVT or PE in obese women,21,36,38 but data in men were less compelling. The Nurses' Health Study showed that the age-adjusted risk ratio for PE women with a body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) 29.0 kg/m2 or higher was 3.2 compared with the leanest category of less than 21.0 kg/m2.36 The Framingham Heart Study showed that metropolitan relative weight was significantly and independently associated with PE among women, but not men.39 However, the Study of Men Born in 1913 showed that men in the highest decile of waist circumference (>100 cm) had an adjusted relative risk for VTE of 3.92 compared with men with a waist circumference less than 100 cm.40 Among 1272 outpatients (men and women), the odds ratio for DVT, comparing obese (BMI> 30 kg/m2) with nonobese patients, was 2.39.41 Others showed a similar odds ratio for DVT of 2.26 compared with nonobese patients.37 BMI correlated linearly with the development of PE in women.42 On the other hand, the Olmsted County, Minnesota casecontrol study found no evidence that current BMI was an independent risk factor for VTE in men or women.33,43 Others did not show obesity to be a risk for VTE in men.21,38 Analysis of the huge database of the National Hospital Discharge Survey44 showed compelling evidence that obesity is a risk factor for VTE.45 Among patients hospitalized in short-term hospitals throughout the United States, in whom obesity was coded among the discharge diagnoses but not defined, 91,000 of 12,015,000 (0.8%) had PE.45 Among hospitalized patients who were not diagnosed with obesity, PE was diagnosed in 2,366,000 of 691,000,000 (0.3%). DVT was diagnosed in 243,000 of 12,015,000 (2.0%) of patients diagnosed with obesity, and in 5,524,000 of 691,000,000 (0.8%) who were not diagnosed with obesity. The relative risk of PE, comparing obese patients with nonobese patients, was 2.18 and for DVT it was 2.50.45 The relative risks for PE and DVT were age dependent. Obesity had the greatest effect on patients less than 40 years of age, in whom the relative risk for PE in obese patients was 5.19 and the relative risk for DVT was 5.20.45 The higher relative risk of obesity in younger patients may have reflected that younger patients uncommonly have multiple

physical examination of the patient.

**2. Obesity and height** 

were immobilized were immobilized for 2 weeks or less.32

1). 19 The incidence of VTE increases dramatically in tandem with the number of risk factors identified in patients.11,21 Most hospitalized patients have at least one risk factor for VTE, and the most recent ACCP review of VTE estimated that approximately 40% have 3 or more risk factors.19 These include fracture (hip or leg), hip or knee replacement, major general surgery, major trauma, and spinal cord injury,11 as well as a history of VTE,11 thrombophilia, 11 inflammatory bowel disease,22 postoperative infection, 19 and cancer.23 Bed rest for more than 72 hours,11,24 use of hormones,11 and impaired mobility11 are additional risk factors. Many of these factors are not simple binary (ie, yes/no) risks. For example, age is a significant risk factor, with the risk approximately doubling with each decade beyond age 40.11,25 It is not sufficient to use a single age cut-off level to define high or low risk.11 Similarly, the incidence of VTE increases with length of surgery.26,27 In addition, Sugerman et al28 found higher rates of VTE in obese patients (mean body mass index, 61) who also had venous stasis syndrome; a simple cut-off level based on a definition of obesity would not capture this increased risk. In fact, Anderson and Spencer11 suggest that the association of risk of VTE and weight alone is a weak one. As noted earlier, hospitalized patients usually have at least 1 risk factor for VTE, and more than a third of hospitalized patients have 3 risk factors or more.19 Risk factor weighting can be used to calculate the risk for an individual patient, and the results may be used to determine several aspects of prophylaxis, such as the length of prophylaxis (including out-of-hospital prophylaxis), selection of prophylactic agent, timing of first dose, and the need for combined use of physical and pharmacologic methods.

Risk assessment typically has taken 1 of 2 approaches, group risk assessment or individual risk assessment. The group risk assessment approach assigns patients to one of a few broad risk categories, whereas individual risk assessment seeks to define risk more accurately by using individualized risk scores.19 The system recommended by the 2001 ACCP guidelines used a group risk assessment in which the type of surgery ("major" vs "minor"), age bracket, and presence of additional risk factors were used to assign patients to 1 of 4 risk groups29; however, this was based on older studies, arbitrary age cut-off levels, and inexact definitions.19 The ACCP has refined this recommendation with a newer one in which patients are assigned 1 of 3 VTE risk levels based on type of surgery, patient mobility, overall risk of bleeding, and moderate/high risk of VTE based on the presence of additional risk factors 19 As the investigators note, this group risk assessment approach ignores the substantial variability in patient-specific risk factors, but it does take into account what they view as the principal risk factor (surgery vs acute medical illness). This approach is most appropriate for patients who fit the criteria of the randomized clinical trials that were used to develop the model; the investigators include a disclaimer for patient groups that have not been included in clinical trials or for types of patients who have not been tested.19 However, the group risk assessment approach recommended by the ACCP may not be appropriate for all individual patients.30 Out-of-hospital prophylaxis is not addressed except for a few very high risk groups (major cancer surgery, total joint replacement).19 It may be more appropriate to use the individual risk assessment approach to identify and evaluate all possible risk factors to determine the true extent of risk for a patient.30 The ACCP guidelines, in fact, point out that "specific knowledge about each patient's risk factors for VTE" is an essential component of the decision-making process when prescribing thromboprophylaxis. 19 Also, if many risk factors are present and a planned procedure is

1). 19 The incidence of VTE increases dramatically in tandem with the number of risk factors identified in patients.11,21 Most hospitalized patients have at least one risk factor for VTE, and the most recent ACCP review of VTE estimated that approximately 40% have 3 or more risk factors.19 These include fracture (hip or leg), hip or knee replacement, major general surgery, major trauma, and spinal cord injury,11 as well as a history of VTE,11 thrombophilia, 11 inflammatory bowel disease,22 postoperative infection, 19 and cancer.23 Bed rest for more than 72 hours,11,24 use of hormones,11 and impaired mobility11 are additional risk factors. Many of these factors are not simple binary (ie, yes/no) risks. For example, age is a significant risk factor, with the risk approximately doubling with each decade beyond age 40.11,25 It is not sufficient to use a single age cut-off level to define high or low risk.11 Similarly, the incidence of VTE increases with length of surgery.26,27 In addition, Sugerman et al28 found higher rates of VTE in obese patients (mean body mass index, 61) who also had venous stasis syndrome; a simple cut-off level based on a definition of obesity would not capture this increased risk. In fact, Anderson and Spencer11 suggest that the association of risk of VTE and weight alone is a weak one. As noted earlier, hospitalized patients usually have at least 1 risk factor for VTE, and more than a third of hospitalized patients have 3 risk factors or more.19 Risk factor weighting can be used to calculate the risk for an individual patient, and the results may be used to determine several aspects of prophylaxis, such as the length of prophylaxis (including out-of-hospital prophylaxis), selection of prophylactic agent, timing of first dose, and the need for combined

Risk assessment typically has taken 1 of 2 approaches, group risk assessment or individual risk assessment. The group risk assessment approach assigns patients to one of a few broad risk categories, whereas individual risk assessment seeks to define risk more accurately by using individualized risk scores.19 The system recommended by the 2001 ACCP guidelines used a group risk assessment in which the type of surgery ("major" vs "minor"), age bracket, and presence of additional risk factors were used to assign patients to 1 of 4 risk groups29; however, this was based on older studies, arbitrary age cut-off levels, and inexact definitions.19 The ACCP has refined this recommendation with a newer one in which patients are assigned 1 of 3 VTE risk levels based on type of surgery, patient mobility, overall risk of bleeding, and moderate/high risk of VTE based on the presence of additional risk factors 19 As the investigators note, this group risk assessment approach ignores the substantial variability in patient-specific risk factors, but it does take into account what they view as the principal risk factor (surgery vs acute medical illness). This approach is most appropriate for patients who fit the criteria of the randomized clinical trials that were used to develop the model; the investigators include a disclaimer for patient groups that have not been included in clinical trials or for types of patients who have not been tested.19 However, the group risk assessment approach recommended by the ACCP may not be appropriate for all individual patients.30 Out-of-hospital prophylaxis is not addressed except for a few very high risk groups (major cancer surgery, total joint replacement).19 It may be more appropriate to use the individual risk assessment approach to identify and evaluate all possible risk factors to determine the true extent of risk for a patient.30 The ACCP guidelines, in fact, point out that "specific knowledge about each patient's risk factors for VTE" is an essential component of the decision-making process when prescribing thromboprophylaxis. 19 Also, if many risk factors are present and a planned procedure is

use of physical and pharmacologic methods.

based on a quality-of-life decision rather than a critical medical need, the patient may come to a different decision about whether to proceed.30 A common misconception among physicians is that individual risk assessment takes longer and is more cumbersome than group risk assessment. However, individual assessment can be accomplished with, for example, a simple assessment form that merely captures information from the history and physical examination of the patient.

Among all patients with PE in the PIOPED II trial 94% had 1 or more of the following assessed risk factors: bed rest within the last month of 3 days or more, travel within the last month of 4 hours or more, surgery within 3 months, malignancy, past history of DVT or PE, trauma of lower extremities or pelvis, central venous instrumentation within 3 months, stroke, paresis or paralysis, heart failure or chronic obstructive pulmonary disease (COPD).31 Immobilization of only 1 or 2 days may predispose to PE, and 65% of those who were immobilized were immobilized for 2 weeks or less.32
