Venous Thromboembolism (VTE)

Disease/Disorder

Definition

• Venous thromboembolism (VTE) refers to blood clots that develop in veins. It includes superficial and deep venous thrombosis (DVT) and pulmonary embolism (PE).
• PE refers to clot within the pulmonary artery or its branches. These blood clots arise from the veins in the limbs or torso, break off and travel through the right side of the heart to lodge in the main pulmonary artery or its branches.
• Saddle PEs can cause shock by formation of a clot where the pulmonary artery bifurcates, occluding flow back to the left ventricle. This occurrence frequently results in sudden death.

Etiology

Virtually all rehabilitation inpatients are in high-risk groups.

Risk factors include

• History of VTE
• Major surgery (lasting > 2 hours) especially of lower limbs
• Major trauma
• Immobility
• Paralysis
• Prolonged hospitalization or nursing home residence
• Long-distance travel
• Cancer
• Increased estrogen states (including from oral birth control pills or hormonal therapies)
• Pregnancy
• Central venous access devices
• Smoking
• Congestive heart failure
• Chronic obstructive pulmonary disease
• Stroke or other brain injury
• Spinal cord injury
• Obesity
• Increased age
• Kidney disease (e.g., nephrotic syndrome)
• Inherited coagulopathies (Factor V Leiden, prothrombin G20210A, anti-thrombin III, protein C, and protein S deficiencies) are found up to 28% of person with venous clots.¹
• Long-term IVC filters

Most DVTs (> 90%) develop in the lower limbs.² Almost all PEs are associated with proximal DVTs (at or above the knee).³ The propagation rate of distal vein DVTs to the proximal veins is approximately 10-15%.⁴

Epidemiology including risk factors and primary prevention

• In the US, the annual incidence of VTE is estimated to affect 1-2 individuals per 1,000 persons, and approximately 20% of patients with VTE die within 1 year, making it the most common preventable cause of hospital-related death.⁵
• It is optimal to diagnose VTE at the stage of DVT, as PE frequently results in sudden death.⁵
• Unfortunately, only ~50% of VTE events found at autopsy were diagnosed clinically prior to death, hence prevention and early diagnosis and treatment are critical.⁶
• Only 33% of inpatients in US hospitals receive appropriate VTE prophylaxis.⁷

Patho-anatomy/physiology

• Virchow’s triad describes the classic pathophysiologic predisposition: stasis, endothelial injury and hypercoagulability.
• These factors disrupt the normal balance between thrombin formation and endothelial thrombolysis, setting off the coagulation cascade by activating factor Xa.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Propagation: distal DVTs isolated to the calf veins below the knee may propagate and become proximal DVTs, involving the popliteal, iliac, or femoral veins. These clots can then break off and travel to the lungs, leading to pulmonary embolism.

Pulmonary embolism: the presentation of PEs can vary, ranging from no symptoms to arrhythmia, pulmonary hypertension, and sudden death.

Chronic manifestations: Post-thrombotic syndrome is a condition of chronic edema, often with venous stasis ulcers, that can arise in a limb after DVT, particularly if the patient is not given compression stockings.

Resolution/recurrence: VTEs resolve with time, and the risk of recurrence is reduced by treatment with anticoagulation. Notably, patients with symptomatic PE are at higher risk of recurrent VTE than patients presenting with only a DVT.⁸

Specific secondary or associated conditions and complications

• Sudden death from PE is the most serious complication. Up to 55% of fatal PE is first diagnosed at autopsy.⁶
• PE, particularly multiple PEs, can result in chronic pulmonary hypertension.
• Post-thrombotic syndrome predisposes to chronic edema and cellulitis.

Essentials of Assessment

History

Diagnosis is challenging, and physical examination findings are often unreliable. Sudden onset calf pain and/or unilateral lower limb calf swelling is the classic presentation of lower extremity DVT. For upper limb DVT, sudden swelling of the arm should trigger investigation, particularly if a central venous access device is or has been in place. For PE, dyspnea is usually the presenting symptom. Tachycardia, tachypnea, and anxiety should also raise concern for acute pulmonary embolus.

Physical examination

• DVT: Unilateral calf edema and tenderness are usually present. Homan’s sign is an increase in calf tenderness when the ankle is dorsiflexed with the knee in full extension. It may be more sensitive than calf tenderness alone.
• PE: There are no specific physical exam findings for PE. Patients frequently demonstrate some degree of hypoxia on pulse oximetry and are often tachycardic and tachypneic. Lungs are usually clear. Peri-oral cyanosis may be present in extreme cases.

Functional assessment

Some functional loss may occur because of edema (DVT) or because of pulmonary symptoms (PE).

Laboratory studies

Some have advocated the use of D-dimer to screen symptomatic patients before ordering an ultrasound (US). This screen may have some utility in the outpatient setting in patients at low risk, when the D-dimer result is negative; however, in postoperative patients, it is of little benefit because the positive predictive value is low, and false positives are frequent. EKG abnormalities including tachycardia are common in cases suspicious for PE, but largely nonspecific. The S1Q3T3 (S wave in lead I, a Q wave in lead III, and T-wave inversion in lead III) finding, although typically associated with PE, is only found in 15-25% of patients ultimately diagnosed with PE.⁹

Imaging

DVT

• The gold standard for the diagnosis of lower limb DVT is venography; however, it is seldom used clinically outside the research setting. This test involves dye injected into a vein via catheter. It is used when ultrasound or other tests are negative but there remains strong suspicion of DVT.³ However, this study carries a risk of creating a DVT.
• Doppler US has almost as high positive and negative predictive values as venography. Because its negative predictive value (99.5%) is even higher when duplex color technology is used it has become the test of choice for patients with suspected DVT. The sensitivity of duplex ultrasound in detecting a proximal DVT in suspected cases is 96.5%.¹⁰
• Surveillance Doppler US: Screening all high-risk patients for VTE with US upon admission to inpatient rehabilitation is generally not considered cost-effective, although some limited evidence exists showing that some asymptomatic DVTs may be found.¹¹

Pulmonary Embolism

• Pulmonary angiography was historically the gold standard for diagnosing PE, but like venography, it is seldom used clinically.¹²
• CT pulmonary angiography (CTPA) has nearly matched the sensitivity and specificity of pulmonary angiography and is far less invasive. All major guidelines and recent reviews recommend CTPA as the first-line imaging modality for suspected PE when there are no contraindications.¹²
• Ventilation-perfusion (V/Q) scintographic studies can have diagnostically definitive results in some situations, but are reserved for patients who have contraindications to CPTA (e.g., renal insufficiency, contrast allergy, pregnancy, or inability to fit into the CT scanner) due to CTPA’s higher diagnostic yield, ability to identify alternative diagnoses, and greater availability.¹²

Professional issues

Undiagnosed PE is one of the most common reasons for malpractice suits against physiatrists.

Rehabilitation Management and Treatments

Available or current treatment guidelines

• The American College of Chest Physicians (ACCP) has established the most widely used guidelines.¹³ The guides are individualized to diagnosis or predict risk of surgical procedure. The most recent update was released in December 2021. Recommendation for treatment of venous thromboembolism (DVT of the leg or PE) is to use a Direct Oral Anticoagulant (DOAC) instead of Warfarin. In patients with acute VTE in the setting of cancer, a DOAC is recommended over low molecular weight heparins (LMWH).⁴
• Other guidelines exist: Alternative guidelines from the American Academy of Orthopedic Surgery (AAOS) reflect the concern among some orthopedic surgeons about the risk of postoperative hematomas in joint replacement patients who are using LMWH for VTE prophylaxis. They focus on hip and knee surgeries. The last guideline release was in 2012.
• Guidelines for the management of VTE in cancer patients can be found in the American Society of Clinical Oncology (ASCO) guidelines, the American Society of Hematology (ASH) guidelines, and the National Comprehensive Cancer Network (NCCN) VTE panel guidelines. The latest ASCO guidelines (2023) state that initial and long-term anticoagulation in cancer patients may involve LMWH or a DOAC but notes an increase in major bleeding risk with DOACs, particularly in gastrointestinal and genitourinary malignancies.¹⁴ The latest ASH guidelines (2021) suggest use of a DOAC instead of LMWH in patients with cancer and VTE, except in patients with high bleeding risk, impaired GI absorption, or significant drug-drug interactions.¹⁵

At different disease stages

Pre-Disease/Prevention

• Complex medical patients: In a meta-analysis of hospitalized internal medicine patients (excluding those with stroke and myocardial infarction), LMWH and Unfractionated Heparin (UFH) were found both effective in preventing VTE, but LMWH was associated with a lower risk of DVT and major bleeding compared to UFH, while efficacy for PE, mortality, and thrombocytopenia were similar.¹⁶
• Neurosurgical patients: A meta-analysis of 18 studies indicated that LMWH could prevent VTE in patients without a contraindication to its use; whereas intermittent compression devices could also prevent VTE when the contraindication existed. Furthermore, UFH had a higher risk of complications.¹⁷
• Data from brain injury model systems revealed only 56% of centers routinely used anticoagulants prophylactically. The same study reported an incidence of fatal PE of 0.42 per practice year, emphasizing the need for guidelines.¹⁸
• VTE is a leading cause of morbidity and mortality following acute spinal cord injury (SCI) and remains a common and costly complication after traumatic SCI. Among trauma patients, individuals with SCI have the highest risk of DVT. Reported rates of VTE vary greatly depending on the technique used (contrast venography or doppler ultrasound). One study of SCI patients using serial compression devices and stockings but no pharmacologic prophylaxis reported a 41% incidence of DVT by ultrasound.¹⁹
• Cancer: The NCCN released guidelines in 2007 recommending VTE prophylaxis in all hospitalized cancer patients undergoing active therapy who do not have contraindications to anticoagulation.
• Orthopedic patients: Joint replacement or major fracture patients, without a personal history of VTE, may have prophylaxis with mechanical prophylaxis plus one of the following: LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated, heparin (LDUH), adjusted-dose vitamin K antagonist or aspirin 325 mg twice daily for 10-14 days. LMWH is the preferred treatment. For hip fractures, apixaban, dabigatran, and rivaroxaban are not recommended.¹³
• Sequential compression devices (SCDs) have some effectiveness in preventing VTE when used alone compared with no intervention, and should be used when contraindications to anticoagulation exist, such as patients with bleeding disorders or those with history of acute intracranial bleeding. SCDs were substantially less effective than pharmacologic prophylaxis but had additional benefit when used in combination with anticoagulation. In stroke patients, no benefit to the use of mechanical prophylaxis has been demonstrated. These need to be used > 18 hours per day to have any benefit.
• Inferior vena cava filters (IVCFs) can be used to prevent DVT from propagating to a PE in patients with contraindications to anticoagulation. However, there is no demonstrated benefit to using them as a primary prophylaxis. Otherwise, IVCFs are not recommended for those using anticoagulation. IVCFs should be removed as soon as medically feasible.⁴

New Onset/Acute

• LMWH enables VTE to be treated with less intensive monitoring than intravenous UFH.
• DOACs are recommended over vitamin K antagonists (e.g., Warfarin), given similar benefit with increased safety.⁴ They are also the drug of choice in patients who do not have renal insufficiency, severe liver disease, or antiphospholipid antibodies.
• The use of IVCFs can be used to prevent propagation of DVT to PE in patients for whom anticoagulation is contraindicated. These filters now are removable where long-term use is not needed. It should be remembered that IVCFs do not treat DVT, and indeed may worsen edema and pain; they frequently lead to post-thrombotic syndrome.⁴
• The choice of anticoagulation necessitates consideration of patient factors (e.g., renal function, anticipated compliance). For example, DOACs may offer comparable efficacy and improved safety, but severe renal impairment or cost may favor the use of Warfarin.⁴Location of treatment: ACCP and ACP guidelines advocate that most cases of DVT, and some cases of PE, can be safely treated in the outpatient setting, and is preferred. The CHEST guidelines recommend outpatient treatment over hospitalization for patients with low-risk PE, if access to medications, outpatient care, and home circumstances is adequate.⁴ The implication for physiatrists is that most patients with acute DVT, and some with hemodynamically stable PE, can be managed on the rehabilitation unit without transfer to acute care.
• Bed rest and compression stockings: Traditionally physicians have recommended bed rest and the removal of compression devices for several days after DVT, for fear of propagation to PE. This approach is being challenged: according to a retrospective study in Italy, DVT patients who were immobilized and did not receive compression devices had a higher risk of developing PE subsequently.²⁰

Subacute/Chronic/Stable Stage

• Duration of treatment: Patients with acute VTE in the setting of transient risk factors should be treated with 3 months of treatment. Patients with acute VTE in the setting of a persistent risk factor or in the absence of a provocation (unprovoked VTE), should be offered extended duration of treatment, with the stop date determined by a discussion of risks vs. benefits and shared decision making with the patient. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulation therapy and do not have a contraindication, aspirin is recommended to prevent recurrent VTE (weak recommendation, low-certainty evidence).⁴
• Compression stockings are not recommended for the prevention of post thrombotic syndrome (formerly post-phlebitic syndrome) but are acceptable for the management of its symptoms. Progressive ambulation is acceptable.⁴

Pre-Terminal or End of Life Care 

N/A

Special Circumstances

Other factors affect the choice of initial or long term (3-24 months) anticoagulation such as:

• Cancer
• Frequency
• Renal and hepatic disease
• Coronary artery disease
• Peptic ulcer disease
• Drug interactions
• Compliance
• Cost
• Fall risk
• Recurrence:
  • Consider increasing the dose of LMWH if already using or switch to LMWH if using Vitamin K antagonists or Direct Thrombin Inhibitors (DTI).

Translation into practice: Practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

• Environmental interventions: early mobilization is an important part of primary prevention and decreasing recurrence.
• Clinical pearls
  • Tachycardia and tachypnea need urgent attention.
  • PE often presents with vague complaints of anxiety.
• Performance improvement in practice
  • Monitor guideline adherence in your inpatient program.
  • Implement order sets for prophylaxis.

Cutting Edge/Emerging and Unique Concepts and Practice

• Personalized: Increasing use of pharmacogenomics and individualized risk assessment tools to tailor anticoagulant choice and duration.²¹
• Risk-based: Ongoing research into optimal duration and intensity of prophylaxis in high-risk populations (e.g., cancer, trauma, orthopedic, and medically ill patients).²¹
• DOACs: Continued expansion of indications, including in select cancer populations, and ongoing trials in populations previously excluded (e.g., severe renal impairment, antiphospholipid syndrome).²¹
• Mechanical prophylaxis: Development of new intermittent pneumatic compression devices and wearable technologies for VTE prevention in patients with contraindications to anticoagulation.²¹
• Artificial intelligence (AI): Use of AI-driven algorithms to improve VTE risk prediction, diagnosis, and adherence to prophylaxis protocols.²²
• Biomarkers: Investigation of novel biomarkers for VTE risk stratification, recurrence prediction, and monitoring of anticoagulant effect.²³

Gaps in the Evidence-Based Knowledge

Duration of prophylaxis is poorly established for many diagnoses. Risk/benefits and cost effectiveness of prophylaxis in the disabled population is poorly established.

References

1. Middeldorp, S., et al., American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv, 2023. 7(22): p. 7101-7138.
2. Heil, J., et al., Deep Vein Thrombosis of the Upper Extremity. Dtsch Arztebl Int, 2017. 114(14): p. 244-249.
3. Bates, S.M., et al., Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e351S-e418S.
4. Stevens, S.M., et al., Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest, 2021. 160(6): p. e545-e608.
5. Lutsey, P.L. and N.A. Zakai, Epidemiology and prevention of venous thromboembolism. Nat Rev Cardiol, 2023. 20(4): p. 248-262.
6. Pineda, L.A., V.S. Hathwar, and B.J. Grant, Clinical suspicion of fatal pulmonary embolism. Chest, 2001. 120(3): p. 791-5.
7. Amin, A.N., et al., Preventing venous thromboembolism in US hospitals: are surgical patients receiving appropriate prophylaxis? Thromb Haemost, 2008. 99(4): p. 796-7.
8. Eichinger, S., et al., Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med, 2004. 164(1): p. 92-6.
9. Ullman, E., et al., Electrocardiographic manifestations of pulmonary embolism. Am J Emerg Med, 2001. 19(6): p. 514-9.
10. Goodacre, S., et al., Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging, 2005. 5: p. 6.
11. Furlan, J.C. and M.G. Fehlings, Role of screening tests for deep venous thrombosis in asymptomatic adults with acute spinal cord injury: an evidence-based analysis. Spine (Phila Pa 1976), 2007. 32(17): p. 1908-16.
12. Expert Panel on Cardiac, I., et al., ACR Appropriateness Criteria(R) Imaging for Pulmonary Embolism, Known Clot. J Am Coll Radiol, 2025. 22(5S): p. S261-S273.
13. Guyatt, G.H., et al., Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. 7S-47S.
14. Key, N.S., et al., Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update. J Clin Oncol, 2023. 41(16): p. 3063-3071.
15. Lyman, G.H., et al., American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv, 2021. 5(4): p. 927-974.
16. Alikhan, R., R. Bedenis, and A.T. Cohen, Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev, 2014. 2014(5): p. CD003747.
17. Collen, J.F., et al., Prevention of venous thromboembolism in neurosurgery: a metaanalysis. Chest, 2008. 134(2): p. 237-249.
18. Carlile, M.C., et al., Deep venous thrombosis management following traumatic brain injury: a practice survey of the traumatic brain injury model systems. J Head Trauma Rehabil, 2006. 21(6): p. 483-90.
19. America, P.V.o., Prevention of venous thromboembolism in individuals with spinal cord injury: Clinical Practice Guidelines for Health Care Providers. 2016.
20. Manganaro, A., et al., A retrospective analysis of hospitalized patients with documented deep-venous thrombosis and their risk of pulmonary embolism. Angiology, 2008. 59(5): p. 599-604.
21. Renner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020;76(18):2142-2154. doi:10.1016/j.jacc.2020.07.070
22. Gu Y, Yang Y, Gao X, Wang Y, Yang L, Wei Y. Application of artificial intelligence in risk assessment and management of venous thromboembolism: scoping review. Front Physiol. 2025;16:1664470. doi:10.3389/fphys.2025.1664470
23. Fu L, Yu J, Chen Z, et al. Integrating machine learning with transcriptome-wide association studies to identify novel predictive biomarkers for venous thromboembolism. Br J Haematol. 2025;207(5):1883-1892. doi:10.1111/bjh.70160

Original Version of the Topic

R. Samuel Mayer, MD. Venous Thromboembolism (VTE). 12/27/2012

Previous Revision(s) of the Topic

R. Samuel Mayer, MD, Mi Ran Shin, MD, W. Bernard Abrams MD. Venous Thromboembolism (VTE). 4/28/2017.

Juan L Asanza, MD, Daniel N Nguyen, MD. Venous Thromboembolism (VTE). 9/1/2022

Author Disclosure

Justin Weppner, DO
Nothing to Disclose

Tyler Shick, MD
Nothing to Disclose