Sections

Overview

Practice Essentials

Venous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum, deep vein thrombosis (DVT) and pulmonary embolism (PE) (see the image below). The spectrum of disease ranges from clinically unsuspected to clinically unimportant to massive embolism causing death.

Venous Thromboembolism (VTE). Helical CT scan of the pulmonary arteries. A filling defect in the right pulmonary artery is present, consistent with a pulmonary embolism.

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Signs and symptoms

Signs and symptoms of thromboembolism include the following:

Acute onset of shortness of breath; dyspnea is the most frequent symptom of PE
Pleuritic chest pain, cough, or hemoptysis (with a smaller PE near the pleura)
Syncope (with a massive PE)
Sense of impending doom, with apprehension and anxiety
Complaints related to signs of DVT, lower-extremity swelling, and warmth to touch or tenderness
Tachypnea (respiratory rate >18 breaths/min)
Tachycardia
Accentuated second heart sound
Fever
Normal findings from lung examination
Cyanosis

See Presentation for more detail.

Diagnosis

Workup for thromboembolism includes the following:

Pulmonary angiography: Diagnostic standard for PE
Ventilation-perfusion scanning: Most common screening technique
Venography: Standard test for validating new diagnostic procedures
Arterial blood gas values on room air: Hypoxemia, elevated alveolar-arterial oxygen gradient
Acid-base status: Respiratory alkalosis
Enzyme-linked immunoassay (ELISA) for D-dimer
Electrocardiography, especially for ruling out myocardial infarction
Chest radiography: Most often normal but occasionally suggestive
Helical (spiral) computed tomography of pulmonary vessels
Doppler ultrasonography of venous system
Echocardiography
Impedance plethysmography: Of limited value when DVT is asymptomatic or distal or when findings are nonocclusive

See Workup for more detail.

Management

Anticoagulant medications include the following:

Heparin or a low-molecular-weight heparin (LMWH)
Subsequent administration of an oral coumarin derivative (typically, warfarin sodium)
Oral factor Xa inhibitors (eg, rivaroxaban)

Thrombolytic options (for initial treatment of patients with acute, massive PE causing hemodynamic instability) include the following:

Tissue plasminogen activator (t-PA; first-choice thrombolytic agent), including the recombinant agents alteplase, reteplase, and tenecteplase
Streptokinase (risk of antibody development)
Urokinase (of limited availability)

Surgical interventions include the following:

Thrombectomy
Embolectomy (limited to massive PE when thrombolysis is contraindicated or other treatments have failed)
Venous interruption (currently rare)

Prevention

Thromboprophylaxis reduces the incidence of DVT and fatal PE and may be achieved by pharmacologic or mechanical means. Medications used for prevention of thromboembolism include the following:

Unfractionated heparin
LMWH
Danaparoid
Warfarin
Direct oral anticoagulants
Aspirin

Mechanical approaches to thromboprophylaxis include the following:

External compression
Early ambulation

See Treatment and Medication for more detail.

Background

Venous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum, deep venous thrombosis (DVT) and pulmonary embolism (PE). PE is the obstruction of blood flow to one or more arteries of the lung by a thrombus lodged in a pulmonary vessel, as shown in the image below. (See Pathophysiology and Etiology.)

Venous Thromboembolism (VTE). Pulmonary embolism within the pulmonary artery.

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PE and DVT can occur in the setting of disease processes, following hospitalization for serious illness, or following major surgery. In 1856, Virchow demonstrated that 90% of all clinically important PEs result from DVT occurring in the deep veins of the lower extremities, proximal to and including the popliteal veins. However, emboli also can originate from the pelvic veins, the inferior vena cava, and the upper extremities. (See Pathophysiology, Etiology, Presentation, and Workup)^{[1, 2, 3, 4, 5]}

Thromboembolic disease is the third most common acute cardiovascular disease, after cardiac ischemic syndromes and stroke. The spectrum of disease ranges from clinically unsuspected to clinically unimportant to massive embolism causing death, and indeed DVT and PE frequently remain undiagnosed because they may not be suspected clinically. Untreated acute proximal DVT causes clinical PE in 33-50% of patients. Untreated PE often is recurrent over days to weeks and can either improve spontaneously or cause death. (See Epidemiology, Presentation, and Workup.)

In a study of Virchow's triad in "silent" DVT, Lurie et al assessed 152 patients who underwent venous stenting for proximal venous outflow obstruction and who had routine hypercoagulation profile testing performed preoperatively.^[6]By history or intraoperative chronic postphlebitic changes (CPPCs), 77 patients (50.7%) were positive for remote DVT; 51 (33.6%) had intraoperative findings of CPPCs without a history of DVT; 20 (13.2%) had intraoperative CPPCs with a history of DVT; and six (3.9%) had a history of DVT without intraoperative findings. Findings of CPPCs were significantly increased among patients with a history of DVT, and intraoperative findings of CPPCs were significantly increased in patients with one or more positive hypercoagulation markers.

Guidelines

Guidelines for the diagnosis and management of VTE have been published by the American Society of Hematology, the American Society of Clinical Oncology (ASCO), the European Society of Anesthesiology (ESA), the American College of Chest Physicians (ACCP), the American Academy of Orthopaedic Surgeons (AAOS), and the International Initiative on Thrombosis and Cancer (ITAC). Go to Guidelines for more information.

AAOS guidelines

The 2011 guidelines from the American Academy of Orthopaedic Surgeons (AAOS) on preventing VTE in patients undergoing elective hip and knee arthroplasty included the following recommendations^{[7, 8]}:

Recommend against routine postoperative duplex ultrasonography screening
Assess risk of previous VTE
Assess risk for bleeding
Suggest discontinuance of antiplatelet agents before undergoing elective hip or knee arthroplasty
Suggest pharmacologic agents and/or mechanical compressive devices for prevention of VTE in those undergoing elective hip or knee arthroplasty who are not at elevated additional risk for VTE or bleeding
Pharmacologic prophylaxis and mechanical compressive devices for those who have had previous VTE and are undergoing elective hip or knee arthroplasty
Mechanical compressive devices for those who have had known bleeding disorder and/or active liver disease and are undergoing elective hip or knee arthroplasty
Patients should undergo early mobilization following elective hip and knee arthroplasty
Use of neuraxial anesthesia for those undergoing elective hip or knee arthroplasty to help limit blood loss
No recommendation can be made for or against the use of inferior vena cava (IVC) filters

Other guidelines

A study by Khokhar et al indicated that there is a lack of uniformity among venous thromboprophylactic guidelines for elective knee arthroplasty. Reviewing 12 guidelines, the investigators found that although almost all of them advocated the use of LMWH and fondaparinux (a synthetic, pentasaccharide anticoagulant), recommendations for other drugs varied, as did drug dosages, duration, and recommendation grades.^[9]

In an article addressing the differences between the antithrombotic guidelines of the American College of Chest Physicians (ACCP) and those of the AAOS, the authors noted that recommendation variations were based on methodology and evidence differences.^[10] With updates to these two more popular VTE guidelines, similar recommendations were offered that focus on minimizing symptomatic VTE and bleeding complications.^[11]

Pathophysiology

A thrombus is a solid mass composed of platelets and fibrin with a few trapped red and white blood cells that forms within a blood vessel. Hypercoagulability or obstruction leads to the formation of a thrombus in the deep veins of the legs, pelvis, or arms.

As the clot propagates, proximal extension occurs, which may dislodge or fragment and embolize to the pulmonary arteries. This causes pulmonary artery obstruction, and the release of vasoactive agents (ie, serotonin) by platelets increases pulmonary vascular resistance. The arterial obstruction increases alveolar dead space and leads to redistribution of blood flow, thus impairing gas exchange due to the creation of low ventilation-perfusion areas within the lung.

Stimulation of irritant receptors causes alveolar hyperventilation. Reflex bronchoconstriction occurs and augments airway resistance. Lung edema decreases pulmonary compliance. The increased pulmonary vascular resistance causes an increase in right ventricular afterload, and tension rises in the right ventricular wall, which may lead to dilatation, dysfunction, and ischemia of the right ventricle. Right heart failure can occur and lead to cardiogenic shock and even death. In the presence of a patent foramen ovale or atrial septal defect, paradoxical embolism may occur, as well as right-to-left shunting of blood with severe hypoxemia.

Etiology

Risk factors for thromboembolic disease can be divided into a number of categories, including patient-related factors, disease states, surgical factors, and hematologic disorders. Risk is additive.

Patient-related factors include age older than 40 years, obesity, varicose veins, the use of estrogen in pharmacologic doses (ie, oral contraceptives or hormone replacement therapy), and immobility.

Disease states such as malignancy, congestive heart failure, nephrotic syndrome, recent myocardial infarction, inflammatory bowel disease, spinal cord injury with paralysis, and pelvic, hip, or long-bone fracture confer increased risk of thromboembolic disease.

Surgical factors are related to procedure type and procedure duration. Among patients who have undergone hip surgery, 50% have a proximal DVT on the same side as the hip surgery. This is thought to be due to a twisting of the femoral vein during total hip replacement. The incidence of DVT is higher in patients who have undergone knee surgery.^[9]

In a study of patients following pelvic surgery, 40-80% had calf DVT, and 10-20% had thigh vein thromboses. Fatal PE developed in 1-5% of patients. The risk for thromboembolic disease has been shown to be increased with coronary artery bypass grafting (CABG), urologic surgery, and neurosurgery.^[12]

One study identified the following four risk factors as being highly predictive of VTE among hospitalized medical patients^[13]:

Previous VTE
An order for bed rest
Peripherally inserted central venous catheterization line
Cancer diagnosis

This four-element risk assessment model was accurate at identifying patients at risk of developing VTE within 90 days and was more effective than the Kucher Score, a risk assessment score.^[13]

Hematologic disorders that increase thromboembolic risk include the following:

Activated protein C resistance (factor V Leiden)

Risk prediction algorithm

A prospective, open cohort study developed a new clinical risk prediction algorithm (QThrombosis) to assess the risk of VTE development. Using routinely collected data from 564 general practices in England and Wales, this study found that independent predictors at 1 and 5 years included the following^[15]:

Age
Body mass index
Smoking status
Hospital admission in past 6 months
History of varicose veins
Congestive cardiac failure
Chronic renal disease
Cancer
Chronic obstructive pulmonary disease
Inflammatory bowel disease
Current prescriptions for antipsychotic drugs

Oral contraceptive use, tamoxifen use, and hormone replacement therapy were noted in the study as independent predictors in women. This risk assessment can help to identify patients at high risk for VTE and may help determine a course of treatment.

United States statistics

The Centers for Disease Control and Prevention (CDC) estimated that over a 3-year period (2007-2009), there was an estimated annual average of 547,596 hospitalizations in which VTE was diagnosed, for patients aged 18 years or older.^{[16, 17]}

Over the same period, for the same age group, an estimated average of 348,558 hospitalizations in which DVT was diagnosed occurred annually, and an estimated average of 277,549 hospitalizations in which PE was diagnosed occurred annually. Among these patients, an estimated average of 78,511 hospitalizations in which both DVT and PE were diagnosed occurred annually.

International statistics

Thromboembolism has a significant impact on morbidity and mortality internationally. A multinational report of European Union countries estimated that the total number of symptomatic, nonfatal VTE events per annum was more than 465,000 cases of DVT and more than 295,000 cases of PE. The authors estimated more than 370,000 VTE-related deaths, of which 7% were diagnosed ante mortem and 34% were sudden fatal PE.^[18]

Age-, sex-, and race-related demographics

Age is a risk factor for thromboembolic disease, being greater in older patients than in younger ones. The risk doubles with each decade in persons older than 40 years.

According to the CDC, the estimated annual average number (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for specific adult age groups^[17]:

Aged 18-39 years - 54,034
Aged 40-59 years - 143,354
Aged 60 years or older - 350,208

The estimated annual average rate (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for specific adult age groups:

Aged 18-39 - 60/100,000 population
Aged 40-49 - 143/100,000 population
Aged 50-59 years - 200/100,000 population
Aged 60-69 years - 391/100,000
Aged 70-79 years - 727/100,000
Aged 80 years or older - 1134/100,000

According to the CDC, the estimated average annual number (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for adult males and females^[17]:

Males - 250,973
Females - 296,623

The incidence of thromboembolism is higher in African Americans than it is in whites, whereas Asians have a lower incidence than do African Americans and whites. PE occurs more frequently in males than in females.

Prognosis

Thromboembolic disease accounts for approximately a quarter of a million hospitalizations in the United States annually and for about 5-10% of all deaths.

About one third of PE cases are fatal. Of these, 67% are not diagnosed ante mortem, and 34% occur rapidly. A high rate of clinically unsuspected DVT and PE leads to significant diagnostic and therapeutic delays, and this accounts for substantial morbidity and mortality.

Studies demonstrate a 95% risk reduction with treatment of thromboembolic disease. There is, however, a risk of recurrence following the discontinuance of treatment that is related to the type and number of risk factors the patient has and whether they persist following completion of treatment. Some 5-7% of all recurrences are fatal.

Patient Education

For the success and ease of outpatient treatment, patients on oral warfarin anticoagulation should be instructed on the impact of dietary choices on treatment goals and the need for frequent monitoring. Instruction on the avoidance of reversible risk factors would be helpful in preventing disease recurrence.

The best approach to patient education is one that starts with open communication with the patient and family, reviewing not only the procedure or planned surgical intervention, but also potential complications.

For patient education information, see the Lungs Center, as well as Pulmonary Embolism, Deep Vein Thrombosis (Blood Clot in the Leg, DVT), and Blood Clots.

Clinical Presentation

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Media Gallery

Venous Thromboembolism (VTE). Pulmonary embolism within the pulmonary artery.
Venous Thromboembolism (VTE). Ventilation-perfusion scan. Left image: Posterior view of normal findings on ventilation scan. Right image: Posterior view of a perfusion scan that reveals a perfusion defect in the left upper quadrant. The defect in the middle of the image is due to the position of the heart.
Venous Thromboembolism (VTE). Helical CT scan of the pulmonary arteries. A filling defect in the right pulmonary artery is present, consistent with a pulmonary embolism.

of 3

Author

Vera A De Palo, MD, MBA, FCCP Medical Director/Consultant, Respiratory Therapy Program, New England Institute of Technology; Consulting Physician, TruCare

Vera A De Palo, MD, MBA, FCCP is a member of the following medical societies: American College of Chest Physicians, Massachusetts Medical Society, Rhode Island Thoracic Society

Disclosure: Nothing to disclose.

Coauthor(s)

Abdallah E Kharnaf, MD Resident Physician, Department of Medicine, Memorial Hospital of Rhode Island, The Warren Alpert Medical School of Brown University

Abdallah E Kharnaf, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Vinod K Panchbhavi, MD, FACS, FAOA, FABOS, FAAOS Professor, Department of Orthopedic Surgery, Chief, Division of Foot and Ankle Surgery, Director, Foot and Ankle Fellowship Program, Department of Orthopedic Surgery, University of Texas Medical Branch School of Medicine

Vinod K Panchbhavi, MD, FACS, FAOA, FABOS, FAAOS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Orthopaedic Association, American Orthopaedic Foot and Ankle Society, Orthopaedic Trauma Association, Texas Orthopaedic Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Styker.

Acknowledgements

Michael J Belanger, MD Clinical Instructor, Department of Orthopedics, Harvard Medical School

Disclosure: Nothing to disclose.

Jegan Krishnan, MBBS, FRACS, PhD Professor, Chair, Department of Orthopedic Surgery, Flinders University of South Australia; Senior Clinical Director of Orthopedic Surgery, Repatriation General Hospital; Private Practice, Orthopaedics SA, Flinders Private Hospital

Jegan Krishnan, MBBS, FRACS, PhD, is a member of the following medical societies: Australian Medical Association, Australian Orthopaedic Association, and Royal Australasian College of Surgeons

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jerome D Wiedel, MD Chair, Professor, Department of Orthopedics, University of Colorado Health Sciences Center

Disclosure: Nothing to disclose.