History and exam
Key diagnostic factors
uncommon
calf swelling
Unilateral leg and thigh swelling can be assessed by measuring the circumference of the leg 10 cm below the tibial tuberosity. If there is a difference in circumference, especially of >3 cm between the extremities, DVT is more likely.
localized pain along deep venous system
Localized pain can be assessed by gently palpating along the path of the deep venous system from groin to adductor canal and in the popliteal fossa.
Other diagnostic factors
common
asymmetric edema
Presence of edema worse on leg with suspected DVT.
prominent superficial veins
Dilated superficial veins over foot and leg (not varicose veins) are a sign of DVT.
uncommon
swelling of the entire leg
Increases pretest probability of diagnosis of DVT.
phlegmasia cerulea dolens
Phlegmasia cerulea dolens is a life- and limb-threatening complication of massive DVT, where swelling and rapid extension of thrombosis can obstruct not only venous outflow but arterial inflow. This leads to sudden and severe ischemic pain, cyanosis, and significant congestion of the affected limb.[40] Patients can quickly become unstable with tachycardia and shock, with complications including massive pulmonary embolism, compartment syndrome, and venous gangrene.[40] Phlegmasia cerulea dolens is a limb- and potentially life-threatening emergency that requires emergency treatment.
Risk factors
strong
recently bed-bound for 3 days or more
This is a component of the Wells score.[19]
Venous stasis and prolonged bed rest are known to increase the risk of venous thromboembolism.
major surgery within the preceding 3 months
Major surgery is a particularly significant risk if the patient required general or regional anesthesia, as this is a component of the Wells score.[19]
Approximately 50% of all incident venous thromboembolism occurs within the first week following major surgery.[29] Reasons include postoperative immobilization, inflammation, underlying comorbidity, and injury to the venous system in selected cases (e.g., total knee replacement).[30]
medical hospitalization within the preceding 2 months
Approximately 20% of all incident venous thromboembolism (VTE) occurs either during a medical hospitalization or within 2 months of a hospitalization of 4 or more days.[3][31]
Reasons include the combination of immobilization with acute and chronic medical comorbidities that are associated with VTE development, such as acute infection, heart failure, stroke, respiratory failure, and inflammatory conditions.[32][33][34] The use of intravenous catheters predisposes to hospital-associated DVT in both the upper and lower extremities.[35][36][37]
active cancer
Active cancer is particularly significant if treatment is ongoing, within 6 months, or palliative; this is a component of the Wells score.[15][19][38][39][40][41]
Many malignancies increase the risk for thrombosis through a variety of mechanisms, including activation of the coagulation system and restriction of flow due to vein compression. DVT rates are likely to be 4- to 7.5-fold higher in patients with cancer than in the general population, and patients with metastatic cancer at the time of diagnosis are at especially increased risk.[15][38][39] Cancer-related therapies including surgery, some chemotherapeutic and biologic agents, and use of vascular access devices also increase the risk of DVT.
Several validated risk prediction tools are available to estimate risk and inform prophylaxis strategies specifically in patients with cancer. Venous thromboembolism (VTE) risk varies between individual patients with cancer and cancer settings; therefore, regular VTE risk evaluation is important for cancer patients, especially during the initiation of antineoplastic therapy or at hospitalization. Individual risk factors such as biomarkers or cancer type do not reliably predict which cancer patients have a high VTE risk.[42]
previous venous thromboembolic event
Previous venous thromboembolism predicts the risk for future events, with the magnitude of the risk being dependent on the presence or absence of provoking factors at the time of the initial event, sex of the patient, and other factors. Recurrence risk may be as high as 15% per year or more in some patients.[43]
recent trauma or fracture
Paralysis, paresis, or recent plaster immobilization of the lower extremities is a component of the Wells score.[19]
Patients with severe trauma are at increased risk of DVT even when the lower extremities are not involved.[44][45]
Patients with lower-extremity injuries that require surgery, such as leg, femur, or hip fracture, are at particularly increased risk, owing to vein injury coupled with effects of immobilization and surgery.[46]
Nonsurgical injury (e.g., a fracture that requires casting) also increases the risk.
increasing age
pregnancy and the postpartum
varicose veins
The presence of varicose veins was associated with a nearly 5-fold increase in the risk for DVT, and nearly 2-fold risk of pulmonary embolism, per 1000 patient-years.[52]
paralysis of the lower extremities
Venous stasis and prolonged bed rest are known to increase the risk of venous thromboembolism.
hereditary thrombophilias
While predictive of an initial venous thromboembolism (VTE) event, the presence of hereditary thrombophilia carries little risk prediction for recurrent VTE and is not considered an important factor in determining whether a patient should continue anticoagulation for secondary prevention following the initial course of treatment.[18] A large number of genetic variants, many of which encode proteins outside the coagulation system, influence the risk of thrombosis.[53] The five "classic hereditary thrombophilias" have the most robust research, and are the focus of guidelines that recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (e.g., preceding surgery) and support testing only in situations that are likely to impact patient management.[54][55][56] The classic hereditary thrombophilias are detailed below.
factor V Leiden
The factor V Leiden (FVL) mutation creates a variant factor V that is resistant to activated protein C. The relative risk of developing venous thromboembolism (VTE; particularly DVT) is approximately 3 to 4 times greater in patients who carry 1 copy of the FVL mutation (heterozygotes) compared with patients without this mutation. However, the absolute lifetime risk of developing VTE is low.
There is a strong interaction between use of oral contraceptives or hormone replacement therapy containing estrogen and presence of FVL, likely because estrogen also confers resistance to activated protein C.[57] The relative risk increase of VTE is approximately 12-fold that of a noncarrier who does not use estrogen.[58]
Homozygous carriers have a substantially higher risk of developing VTE compared with heterozygotes.
FVL carriers appear to have increased risk for DVT only, not for pulmonary embolism, an observation called the “factor V Leiden paradox."[59]
prothrombin gene G20210A mutation
The prothrombin gene mutation is caused by a single nucleotide polymorphism (G20210A). Affected patients produce an excess amount of prothrombin. The relative risk of developing venous thromboembolism (VTE) is approximately 4 times greater than for the unaffected population, but the absolute risk of thrombosis remains low.
There is a strong interaction between use of oral contraceptives or hormone replacement therapy containing estrogen and presence of the prothrombin variant, with an approximately 7-fold increase in the risk of VTE.[58]
Homozygous carriers of the prothrombin gene mutation have substantially greater risk of developing VTE compared with heterozygotes.
protein C or protein S deficiency
Patients with a well-defined deficiency in protein C or protein S have a 5- to 6-fold greater risk of developing venous thromboembolic events, although the magnitude of this risk varies according to the degree of functional loss present.[58] The absolute risk of first pregnancy-associated venous thromboembolism is 7.8% in protein C-deficient women and 4.8% in protein S-deficient women.[60] Thrombosis risk increases in a multiplicative fashion in the presence of other thrombophilic disorders. Both disorders are rare.
antithrombin deficiency
The prevalence of antithrombin deficiency disorders is low in cohorts of patients with venous thromboembolism (VTE; <1%). The magnitude of thrombosis risk varies depending on the degree of functional loss present. The absolute risk of first pregnancy-associated VTE in antithrombin-deficient women is 16.6%.[60]
antiphospholipid syndrome
Defined as an association of persistently detectable antiphospholipid antibodies with specified clinical features consisting of thrombosis and/or pregnancy-related morbidity, antiphospholipid syndrome is often over-diagnosed, likely due to the relatively complex criteria for diagnosis and the possibility of false-positive laboratory tests.[61]
In contrast to the hereditary thrombophilias, antiphospholipid syndrome likely predicts a higher risk for both initial and recurrent venous thromboembolism (VTE), and may be useful in informing decisions regarding use of anticoagulation for secondary prevention after the initial treatment of a VTE event.[62] Antiphospholipid antibodies have been reported in up to 14% of patients presenting with a VTE.[63]
medical comorbidity
Underlying mechanisms vary with the type of comorbidity, but there is usually vascular inflammation or stasis, alone or in combination.
Increased venous thromboembolism risk occurs especially with inflammation, infection, and immobility.
Case reports and small series show greater incidence in patients with sickle cell anemia, inflammatory bowel disease, Behcet disease, HIV, primary pulmonary hypertension, hyperlipidemia, diabetes mellitus, myeloproliferative diseases, and others, including systemic lupus erythematosus.[64]
Several medical disorders, especially heart failure, respiratory disease, acute ischemic stroke, and acute infections, are associated with hospital-acquired DVT, though the incidence of DVT continues to accumulate for about 2 months after hospital admission.[32][33][34]
Liver disease, even when causing prolongation of coagulation times, increases the risk for thrombosis.[65]
Mechanical ventilation has been associated with increased DVT in many studies of critically ill patients, though may be a marker of disease severity and underlying respiratory disease.[10][66][67]
use of specific drugs
The absolute risk of developing a DVT in women who take estrogen-containing oral contraceptives is low. The risk of developing an oral contraceptive-related DVT is associated with the presence of a classic thrombophilia and is also associated with obesity and smoking. Risk is greatest in the first year of use.
For contraceptives, all preparations that contain estrogen are associated with risk for venous thromboembolism (VTE). Mechanism of delivery (oral, transdermal, transvaginal) and the "generation" of oral combined contraceptives are associated with broadly similar risks.[68][69] However, oral contraceptive pills containing third-generation progestins (e.g., desogestrel) or fourth-generation progestins (e.g., drospirenone) may be associated with greater risk of VTE compared with levonorgestrel.[70][71] When used for the indication of hormone replacement, the transdermal route appears to confer less risk than the oral route.[57][68][69]
Tamoxifen and raloxifene are associated with a 2- to 3-fold relative risk of developing DVT, particularly in patients with a thrombophilic condition, such as factor V Leiden.
Thalidomide most commonly causes DVT when used as a cancer chemotherapeutic agent. Many other chemotherapeutic agents can also increase the risk. Concomitant prophylaxis is suggested for certain diseases and regimens.[72]
Erythropoietin is associated with an increased risk of DVT in cancer patients.
Patients who develop antibodies to adalimumab (a tumor necrosis factor alpha inhibitor) frequently develop venous thrombosis.[73]
Androgen-deprivation therapies used in prostate cancer increase VTE risk between about 1.5- and 2.5-fold depending upon the agent.[74]
Testosterone replacement therapy, in men both with and without demonstrable hypogonadism, has been controversial, with some studies reporting association with up to a 2-fold increased VTE risk, while others report no association.[75][76]
Nonsteroidal anti-inflammatory drugs (NSAIDs), as a class, are associated with an increased rate of VTE. Risk attributable to individual NSAIDs is unknown.[77][78]
Antidepressant use in women was associated with an increased risk for VTE (RR 1.37), whereas there was not a significant increase in VTE risk in women with depression managed without drugs.[79]
weak
obesity
Randomized clinical trials and retrospective cohort studies have shown that high body mass index (especially >30 kg/m²) is associated significantly with DVT development.[47][80][81]
Mechanisms may include relative immobilization, reduced venous flow rates, underlying inflammatory state, and greater frequency of coexisting comorbidities.
cigarette smoking
The Emerging Risk Factors Collaboration (ERFC; 731,728 participants) found a correlation between current smoking and the risk of venous thromboembolism, with a hazard ratio of 1.38.[47]
recent long-duration air travel
The absolute risk with air travel appears to be small.[82] The risk appears to be increased in patients with an elevated baseline risk of venous thromboembolism (VTE) such as those with a previous VTE, recent surgery or trauma, obesity, limited mobility, or advanced age.[4][82]
The duration of travel associated with increased risk is uncertain, but longer than about 4 hours is likely associated with elevated risk.[82][83]
family history of venous thromboembolism
central venous catheterization
Studies of cancer patients have estimated the overall rate of catheter-related thrombosis to be between 14% and 18%.[36]
Among nonmetastatic invasive breast cancer patients, an incidence rate of 2.18/100 patient-months has been reported for central venous catheter-related venous thromboembolism (VTE).[85]
Central venous catheters are also associated with VTE in noncancer patients. VTE is increased in intensive care unit patients with central venous catheters, and the risk is further increased with multiple catheters.[37]
Different types of central venous catheters, catheter size, and location of placement affect the risk of catheter-associated VTE.[35]
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