History and exam
Key diagnostic factors
common
uncommon
presyncope or syncope
hypotension (systolic BP <90 mmHg)
Feature of shock.
Present in 3% of patients with confirmed PE.[88]
Indicates central PE and/or a severely reduced hemodynamic reserve.
Other diagnostic factors
common
uncommon
unilateral swelling/tenderness of calf
A feature elicited if deep venous thrombosis is present.
hemoptysis
elevated jugular venous pressure
May be elicited if cor pulmonale is present.[92]
sternal heave
May be elicited if cor pulmonale is present.[93]
accentuated pulmonary component of S2
May be elicited if cor pulmonale is present.
Risk factors
strong
diagnosis of deep vein thrombosis
major surgery within the preceding 3 months
Approximately 18% of all incident cases of venous thromboembolic events occur within 3 months of major surgery. Reasons include postoperative immobilization, inflammation, underlying comorbidity, and injury to the venous system in selected cases (e.g., total knee replacement).[32] Present in 29% with confirmed PE.[30]
medical hospitalization within the preceding 2 months
Approximately 20% of all incident venous thromboembolic (VTE) events develop either during a medical hospitalization or within 2 months of a hospitalization of ≥4 days.[33][34] 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.[35][36][37][38] The use of intravenous catheters predisposes to hospital-associated deep vein thrombosis, both in the upper and lower extremities.[39] Present in 28% with confirmed PE.[30]
active cancer
Ovarian, uterine, prostate, and brain cancers are most commonly associated with death due to PE.[40] Venous thromboembolism (VTE) 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.[41][42] Cancer-related therapies (including surgery, some chemotherapeutic and biologic agents, and use of vascular access devices) also increase the risk of VTE. Present in 22% with confirmed PE.[30]
Several validated risk prediction tools are available to estimate risk and inform prophylaxis strategies specifically in patients with cancer. 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 like biomarkers or cancer type do not reliably predict which cancer patients have a high VTE risk.[43]
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.[44] Present in 25% with confirmed PE.[30]
recent trauma or fracture
Patients with severe trauma are at increased risk of deep vein thrombosis, even when the lower extremities are not involved.[45][46] 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.[47] Nonsurgical injuries (e.g., a fracture that requires casting) also increases the risk. Present in 11% with confirmed PE.[30]
increasing age
The risk of venous thromboembolism, especially of a first episode, increases exponentially with age.[32][33][48] Reasons likely include increased medical comorbidities, declining mobility, and perhaps age-related changes in coagulation.
The risk of direct mortality from PE increases with age.[49] Age-specific mortality rates double for every 10 years starting at age 25.[40]
pregnancy and postpartum
There is a more than fourfold increased risk of thrombosis throughout gestation, and this risk may increase during the postpartum period.[50][51][52] While the relative risk for venous thromboembolism during pregnancy and the postpartum is substantially elevated, the absolute risk in pregnancy remains low.
paralysis of the lower extremities
Venous stasis and prolonged bed rest are known to increase the risk of venous thromboembolic event.[53]
factor V Leiden mutation
The factor V Leiden (FVL) mutation creates a variant factor V that is resistant to activated protein C. The relative risk of developing venous thromboembolic events (particularly deep vein thrombosis [DVT]) is approximately 3-4 times greater in patients who carry one copy of the FVL mutation (heterozygotes) compared with patients without this mutation. However, the absolute lifetime risk of developing venous thromboembolism (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. The relative risk increase of VTE is approximately 12-fold compared with that of a noncarrier who does not use estrogen.[54]
Homozygous carriers have 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".[55]
While predictive of an initial VTE event, the presence of a 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.[21] Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (such as preceding surgery).[56]
prothrombin 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 four times greater than 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 sevenfold increase in the risk of VTE.
Homozygous carriers of the prothrombin gene mutation have substantially greater risk of developing VTE compared with heterozygotes.
While predictive of an initial 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.[21] Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (such as preceding surgery).[56][57]
protein C and protein S deficiency
Patients with a well-defined deficiency in protein C or protein S have a five- to sixfold greater risk of developing venous thromboembolic events, although the magnitude of this risk varies according to the degree of functional loss present.[51] The absolute risk of first pregnancy-associated venous thromboembolism (VTE) in protein C-deficient women is 7.8% and 4.8% in protein S-deficient women.[58] Thrombosis risk increases in a multiplicative fashion in the presence of other thrombophilic disorders. Both disorders are rare.
While predictive of an initial VTE event, the presence of hereditary thrombophilia carries little risk prediction for recurrent VTE, and is not considered suggested as an important factor in determining whether a patient should continue anticoagulation for secondary prevention following the initial course of treatment.[21] Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (such as preceding surgery).[56][57]
antithrombin deficiency
The prevalence of antithrombin (AT) deficiency disorders is low in cohorts of patients with venous thromboembolic events (<1%). The magnitude of thrombosis risk varies depending on the degree of functional loss present. The absolute risk of first pregnancy-associated venous thromboembolism (VTE) in antithrombin-deficient women is 16.6%.[58]
While predictive of an initial VTE event, the presence of hereditary thrombophilia carries little risk prediction for recurrent VTE, and is not considered suggested as an important factor in determining whether a patient should continue anticoagulation for secondary prevention following the initial course of treatment.[21] Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (such as preceding surgery).[56][57]
antiphospholipid antibody syndrome
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.[59] Antiphospholipid antibodies have been reported in up to 14% of patients presenting with a VTE.[60]
Defined as an association of persistently detectable antiphospholipid antibodies with specified clinical features consisting of thrombosis and/or pregnancy-related morbidity, antiphospholipid antibody syndrome is often over-diagnosed, likely due to the relatively complex criteria for diagnosis and the possibility of false-positive laboratory tests. Criteria have been updated and clarified.[61]
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.[62]
Several medical disorders, especially heart failure, respiratory disease, acute ischemic stroke, and acute infections, are associated with hospital-acquired deep vein thrombosis (DVT), though the incidence of venous thromboembolism (VTE) continues to accumulate for at least 1 month after hospital admission.[35][36][37][38]
Liver disease, even when causing prolongation of coagulation times, increases the risk for thrombosis.[63] Mechanical ventilation, which may be a marker of disease severity and underlying respiratory disease, has been associated with increased VTE in many studies of critically ill patients.[64][65][66]
Coronavirus disease 2019 (COVID-19), an infection caused by the SARS-CoV-2 virus, has been associated with risk for VTE; the risk for PE may predominate over the risk for DVT.[18]
use of specific drugs
The absolute risk of developing a deep vein thrombosis (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.[67][68] When used for the indication of hormone replacement, the transdermal route appears to confer less risk than the oral route.[67][68]
Tamoxifen and raloxifene are associated with a two- to threefold 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.[69]
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.[70]
Androgen deprivation therapies used in prostate cancer increase VTE risk between about 1.5- and 2.5-fold depending upon the agent.[71]
Testosterone replacement therapy, both in men with and without demonstrable hypogonadism, has been associated with twofold increased VTE risk.[72]
Nonsteroidal anti-inflammatory drugs (NSAIDs), as a class, are associated with an increased rate of VTE. Risk attributable to individual NSAIDs is unknown.[73][74]
weak
obesity (BMI ≥29 kg/m²)
Randomized clinical trials and retrospective cohort studies have shown that high body mass index (especially >30 kg/m²) is associated significantly with venous thromboembolism development.[48][75] Mechanisms may include relative immobilization, reduced venous flow rates, underlying inflammatory state, and greater frequency of coexisting comorbidities. Present in 29% of patients with a diagnosed PE.[30]
cigarette smoking
The Emerging Risk Factors Collaboration (ERFC; 731,728 participants) found a correlation between current smoking and the risk of venous thromboembolism (hazard ratio of 1.38). Present in 18% with confirmed PE.[30]
recent long-distance air travel
The absolute risk with air travel appears to be small. 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.
The duration of flight associated with increased risk is uncertain, but flights longer than about 4 hours are likely associated with elevated risk.[76]
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%.[78]
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).[79]
Central venous catheters are also associated with VTE in non-cancer patients. VTE is increased in intensive care patients with central venous catheters, and the risk is further increased with multiple catheters.[80]
Different types of central venous catheters, catheter size, and location of placement, affect the risk of catheter-associated VTE.[39]
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