Deep Venous Thrombosis Risk Factors


Definition/Introduction

The pathophysiology of venous thrombosis has been famously described by Rudolf Virchow, known as the 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 the 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, prevention of thrombotic events. Preventive strategies such as the use of pneumatic devices and prophylactic anticoagulation are a standard of care in hospital medicine, and such strategies are based on the identification of the underlying risk factors in an individual patient. 

Issues of Concern

Deep Venous Thrombosis Risk Factors

DVTs either can 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 compared to Caucasians. [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 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 odd's ratio up to more than 80, depending on the underlying inherited risk present. [8] Below, we discuss the identified acquired risk factors for the development of 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. 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. [9] 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 2-4 folds. [10] 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. [11] A past history of DVT is a risk for recurrent DVT and a past 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, the use of some chemotherapy agents, central venous catheters, and the need for surgery for malignancies also contribute to the risk for thromboembolic events. 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 greatest 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. Use of thalidomide or lenalidomide for multiple myeloma treatment has also been identified as a risk factor.[12][13][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]

Pregnancy

Pregnancy is a well-known risk factor for DVTs, due to the hypercoagulable state as well as 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.

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. [18] DVTs are the most common thrombotic complication of APLSand are frequently recurrent. [18] In one study, APLAs were present in 14% of patients with recurrent VTEs. [19]

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's 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 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 risk factor for DVTs 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. [20] 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 the risk of a patient having a DVT. [21] 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 serves to provide guidance on the “next best step” for the patient workup, be it D-dimer or ultrasound doppler imaging. This system, however, serves as evidenced-based medicine and guided care based on the study of risk factors for DVT. While it is not all-inclusive, it provides a broad grouping of the most common risk factors.

The criteria give one point to these components: Active cancer or treated cancer within the past 6 months, bedridden for more than 3 days or major surgery within the last 4 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.

Clinical Significance

The knowledge and identification of these risk factors are of importance not only in early recognition and treatment of DVTs, but also prevention of initial and subsequent DVTs. The presence or absence of these risk factors can guide the use of prophylactic measures such as prophylactic anticoagulation therapy in hospitalized patients. Further, identification of inherited risk factors can be crucial to the use of appropriate long-term anticoagulation therapy when indicated to prevent future DVTs and complications of DVTs such as PEs. 


Article Details

Article Author

Kevin McLendon

Article Author

Amandeep Goyal

Article Author

Pankaj Bansal

Article Editor:

Maximos Attia

Updated:

4/22/2021 5:03:28 PM

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