Definition/Introduction
The pathophysiology of venous thrombosis has been famously described by Rudolf Virchow, known as Virchow's triad, which includes stasis, endothelial injury, and hypercoagulability.[1] Venous thrombosis can be superficial venous thrombosis or deep venous thrombosis (DVT); the latter will be the focus of this article. While the most common origins are in the extremities, where the lower extremity is greater than the upper extremity, venous thrombotic events can occur at other vascular areas such as mesentery, pelvis, cerebral, portal tract, etc. DVTs, on their own, can cause morbidity due to postthrombotic syndrome involving local tissue injury. The most concerning complication with high mortality is associated with pulmonary embolism (PE) secondary to venous thromboembolism (VTE).
Several risk factors, both inherited and acquired, have been specifically studied and associated with venous thrombotic events, and identification of such risk factors can improve diagnostic approaches and, more importantly, the prevention of thrombotic events. Preventive strategies such as using pneumatic devices and prophylactic anticoagulation are a standard of care in hospital medicine, and such strategies are based on identifying the underlying risk factors in an individual patient.
Issues of Concern
Deep Venous Thrombosis Risk Factors
DVTs can either be provoked or unprovoked. Provoked thromboembolisms can be associated with known risk factors, most of which are time-limited, while unprovoked may indicate an increased tendency to clot. Most DVTs diagnosed in the emergency department are unprovoked and carry an increased risk of recurrence versus provoked: 15% versus 5% over the next 12 months. Risk factors for DVTs can be broadly classified as inherited or acquired, and up to 80% of patients experiencing a DVT have at least one and often multiple identifiable risk factors.[2]
Often patients with inherited thrombophilias are unaware of their condition until diagnosed with their first VTE. While their condition increases the risk of occurrence against the general population, their risk of recurrence is the same as those with unprovoked DVTs. The high number of unprovoked cases may be due to undiagnosed thrombophilias.
The incidence of VTEs is 30% to 100% higher in African-Americans than in White race individuals.[3][4] There is no gender predominance of DVTs; however, men are more likely to experience recurrent DVTs.[5] The risk of DVTs increases with advancing age, partially also due to an increase in the prevalence of medical conditions and other risk factors for DVTs in the elderly population. Smoking and obesity both have been associated with a higher risk for DVTs.[6][7]
Acquired
Several risk factors can contribute to the development of DVTs, and more than 50% of patients who suffer from a DVT have more than one acquired risk factor.[2] Further, the presence of an underlying inherited risk, in addition to a major medical illness or acquired risk factor, increases the risk for DVT by an odds ratio up to more than 80, depending on the underlying inherited risk present.[8] Below, we discuss the identified acquired risk factors for developing DVTs.
Surgeries, Trauma, and Immobilization
All surgeries, especially major orthopedic and neurovascular surgeries, are associated with a significantly higher risk of DVTs and PEs, especially in individuals with other risk factors such as advancing age, prior DVTs, and medical illnesses.[9] Prolonged surgical times and post-surgical immobilization times are further associated with increased risk for DVTs. Major, as well as minor trauma, confers significant risk for DVTs due to immobilization as well as anatomic risk.[10]
The 4-year recurrence of surgically provoked DVT is 5 to 11%, depending on the procedure. Immobilization associated with prolonged travel, by air or ground, increases the risk of DVTs by 2 to 4 folds.[11] Immobilization associated with other medical conditions, such as hemiplegia due to stroke, also increases the risk of DVTs.
Prior Thromboembolism
History of a prior thromboembolic event is a significant risk for recurrence, especially in patients with unprovoked DVTs and those with inherited or permanent risk factors.[12] A history of DVT is a risk for recurrent DVT, and a history of PE is a risk for recurrent DVT.
Malignancy
Malignancies are associated with hypercoagulability. In the cancer patient, there are a host of factors that determine the thrombogenic potential. In general, the larger the tumor and the less differentiated the cell line, the higher the risk. Further, using some chemotherapy agents, central venous catheters, and the need for surgery for malignancies also contribute to the risk of thromboembolic events. Venous thrombotic events may be as high as 12% with central venous catheters.[13]
Solid-organ malignancies (lung, pancreas, colorectal, kidney, prostate, etc.), as well as hematological malignancies (myeloproliferative neoplasms such as leukemias and myelomas), are associated with a high risk of VTEs. Metastatic cancers, acute leukemias, and myeloma carry the most significant risk. The following cancers are also known for higher thromboembolic potential: pancreatic, ovarian, stomach, renal, adenocarcinoma, glioblastoma, metastatic melanoma, and lymphoma.
Advanced breast or breast cancer treated with chemotherapy has a 10% rate of clinically significant VTE. Clotting risk in cancers treated with chemotherapy is highest during the induction phase, especially when treated with fluorouracil, tamoxifen, or L-asparaginase. Regardless of tumor stage, chemotherapy adjunctive red blood cell growth factors (EPO) increases risk. The use of thalidomide or lenalidomide for multiple myeloma treatment has also been identified as a risk factor.[14][15][16]
While known malignancies are present in most cases of malignancy-associated VTEs, thromboembolism can precede the diagnosis of malignancy as well.[17] In a Danish study, 78 percent of cancers were diagnosed before the event.[18]
Pregnancy
Pregnancy is a well-known risk factor for DVTs due to the hypercoagulable state and the obstruction of the inferior vena cave by the uterus. The risk is greatest in the post-partum period and in women with multiple pregnancies. The presence of other risk factors such as antiphospholipid antibodies, inherited thrombophilias, obesity, increased maternal age, hypertension, diabetes mellitus, smoking, and obesity further increases the risk. The estimated age-adjusted incidence of VTE is 5 to 50 times higher in pregnant versus non-pregnant women.
Antiphospholipid Antibody Syndrome (APLS)
The presence of antiphospholipid antibodies (APLA) is associated with an increased risk of arterial and venous thrombosis involving any organ system. DVTs are the most common thrombotic complication of APLS and are frequently recurrent.[19] In one study, APLAs were present in 14% of patients with recurrent VTEs.[20]
Chronic Medical Conditions
Several medical conditions have been associated with DVTs, including:
- Cardiac: Atherosclerosis, heart failure, hypertension, dyslipidemia
- Renal: Chronic kidney disease, renal transplant, nephrotic syndrome, microalbuminuria
- Hematological: Polycythemia vera, paroxysmal nocturnal hemoglobinuria, hyperhomocysteinemia
- Rheumatological: Behcet disease, rheumatoid arthritis, systemic lupus erythematosus, Antineutrophil cytoplasmic antibodies-associated vasculitis
- Gastrointestinal: Inflammatory bowel disease
- Infections: Sepsis, coronavirus disease 2019, tuberculosis
- Respiratory: Asthma, obstructive sleep apnea
- Endocrine: Polycystic ovary syndrome, diabetes mellitus
Iatrogenic
Several drugs have been associated with an increased risk of DVTs, contraceptive agents being the most important, especially in young women. Hormone replacement therapy in postmenopausal women is also associated with an increased risk of DVTs. Other drugs implicated as a DVT risk factor include glucocorticoids (especially systemic), tamoxifen, testosterone, heparin (heparin-induced thrombocytopenia), and antidepressants. Intravenous drug use has been associated with DVTs due to local trauma and irritation caused to femoral veins when injected in the lower extremities.
Inherited Risk Factors
While several inherited hypercoagulable disorders leading to a risk of DVT have been identified, the most common are factor V Leiden mutation and prothrombin gene mutation, which account for more than 50% of all inherited thrombophilic disorders. Patients can have more than one inherited thrombophilic disorder, and factor V Leiden mutation has been known to co-exist with protein C and protein S deficiency. Further, inherited thrombophilic disorders may also co-exist with acquired risk factors in a patient. The presence of more than one inherited thrombophilic disorder or co-existence of inherited and acquired risk factors poses a greater risk for DVT than either one alone.[21] Identified inherited thrombophilic disorders include:
- Factor V Leiden mutation
- Prothrombin gene mutation
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
- Dysfibrinogenemia
- Factor XII deficiency
- Hyperhomocysteinemia
- Non-O blood group
Risk Factor Stratification
In clinical practice, the Wells Criteria is often utilized to stratify a patient's risk of DVT.[22] It is pertinent to note that the criteria are intended to use in those patients in whom DVT is clinically suspected and is not a diagnostic criterion but a risk stratification. The scoring provides guidance on the "next best step" for the patient workup, be it D-dimer or ultrasound doppler imaging. This system, however, served as evidenced-based medicine and guided care based on the study of risk factors for DVT. While it is not all-inclusive, it broadly groups the most common risk factors.
The criteria give one point to these components: Active cancer or treated cancer within the past six months, bedridden for more than three days or major surgery within the last four weeks, calf swelling greater than 3 cm more than contralateral leg 10 cm below the tibial tuberosity, collateral superficial veins present, diffuse leg swelling, localized tenderness along with the deep venous system, pitting edema which is greater in the symptomatic leg, paralysis or immobilization of lower extremity, and previous DVT. It gives minus 2 points if an alternate diagnosis is likely.
The sum scores are then classified as low risk (0), medium risk (1 to 2), and high risk (3 or more). Per the originating studies, a low risk is equivalent to a 5% risk, and a negative D-dimer is sufficient to rule out DVT. Medium risk carries a 17% likelihood, and either a high-sensitivity D-dimer can be used or forgone in place of a Doppler study, with a single negative test being sufficient. High risk has a prevalence of 17 to 53%, and US doppler is recommended, although it may not be sufficient. A follow-up 1-week Doppler may be indicated to prevent missed events. If both D-dimer and Doppler are negative, it is considered sufficient to rule out DVT, even in high-risk patients.
Again, it is important to remember that this is a guide and cannot replace clinical judgment. Also, specific criteria such as the Wells criteria for pulmonary embolism (PE) or the Pulmonary Embolism Rule-Out Criteria (PERC) shall be used when there is a concern for PE.
Deep Venous Thrombosis Risk Factors