The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on how to diagnose and manage pulmonary embolism and deep vein thrombosis.

Cancer associated venous thromboembolism (VTE) is the 2nd leading cause of death in cancer patients and they have a 4-7 fold increase in risk of developing a VTE compared to those without cancer (1). A VTE can be described as a deep vein thrombosis (DVT), which usually starts in the distal lower limb such as the calf, and it can move to the pulmonary system as which point it is called a pulmonary embolism (PE). These complications are common and can cause significant mortality and morbidity burden to patients, in addition to the financial and resource strain it puts on the healthcare system.

The increased incidence of VTE in cancer is due to disruptions in Virchow’s triad, which attributes blood clotting to 3 factors: venous stasis, endothelial dysfunction, and a hypercoagulable state (2). Venous stasis can occur secondary to prolonged periods of immobility, especially as morbidity from cancer increases. Additionally, tumours can compress the vasculature, impairing venous return. There are many ways hypercoagulability is caused by cancer cells. One way is malignant cells themselves becoming pro-coagulable, and they can also cause healthy cells to become hypercoagulable (2). Cancer cells undergo countless genetic mutations that can result in expression of adhesion molecules on their surface, they change the surrounding cellular environment by secreting cytokines that activate tissue factor expression on healthy cells, and they secrete procoagulant particles (3). Each of these mechanisms contribute to at least one of the 3 factors in Virchow’s triad, increasing the risk of clot formation. Recognizing patients with the following risk factors is vital to prevention and management of cancer-associated VTE. Additionally, it’s important to understand how these risk factors are dynamic and patients require re-evaluation over time.

Screening and Diagnosis

Screening for risk

The Khorana Risk Model is a validated screening tool used to assess a patient’s risk of VTE (4). It helps guide decisions on whether or not a person with cancer should receive prophylactic antithrombotic therapy. The score translates to the risk of VTE at 2.5 months follow-up. Patients who score ≥3 (high risk) should be considered for VTE prophylaxis therapy (4).

Interpretation of Khorana scores:

• Low risk = 0 (0.3% VTE rate at 2.5 month follow-up)
• Moderate risk = 1-2 (2.0% VTE rate at 2.5 month follow-up)
• High risk ≥ 3 (6.7% VTE rate at 2.5 month follow-up)
  

Screening for diagnosis and treatment

The Wells score is a set of criteria used to determine a pre-test probability of either a DVT or PE when there is clinical suspicion. It is not diagnostic, but helps to guide what further investigations are needed and those that will be most beneficial.

Interpretation of Wells score for pre-test probability of PE

• PE likely >4 (37.1%)
• PE unlikely ≤ 4 (12.1%)
  

Interpretation of Wells score for pre-test probability of DVT

• DVT likely >1 (28%)
• DVT unlikely ≤ (6%)

Screening for risk

The Khorana Risk Model is a validated screening tool used to assess a patient’s risk of VTE (4). It helps guide decisions on whether or not a person with cancer should receive prophylactic antithrombotic therapy. The score translates to the risk of VTE at 2.5 months follow-up. Patients who score ≥3 (high risk) should be considered for VTE prophylaxis therapy (4).

Interpretation of Khorana scores:

• Low risk = 0 (0.3% VTE rate at 2.5 month follow-up)
• Moderate risk = 1-2 (2.0% VTE rate at 2.5 month follow-up)
• High risk ≥ 3 (6.7% VTE rate at 2.5 month follow-up)
  

Screening for diagnosis and treatment

The Wells score is a set of criteria used to determine a pre-test probability of either a DVT or PE when there is clinical suspicion. It is not diagnostic, but helps to guide what further investigations are needed and those that will be most beneficial.

Interpretation of Wells score for pre-test probability of PE

• PE likely >4 (37.1%)
• PE unlikely ≤ 4 (12.1%)
  

Interpretation of Wells score for pre-test probability of DVT

• DVT likely >1 (28%)
• DVT unlikely ≤ (6%)

Pulmonary embolism usually presents with shortness of breath and tachycardia, but other variable features such as pleuritic chest pain, cough, and symptoms of a DVT can also be present. In the context of clinical suspicion and a likely pre-test probability, the next steps in investigation and diagnosis are D-dimer and imaging (e.g. VQ scan, CT Scan) (7). As a general rule, a D-dimer > 500 ng/mL is considered positive, however the cut off increases with increasing age and it is recommended to use an age-adjusted D-dimer (age x 10) after 50 years old (2).

A DVT often presents with swelling or edema, pain, redness and warmth that is unilateral. The extent of the extremity affected depends on the location of the DVT. The entire leg could be affected if it is more proximal, whereas only the lower leg will be affected if it is located more distally (8). If a DVT is suspected, a Doppler Ultrasound is the imaging modality of choice.

Prophylaxis

Primary prophylaxis is indicated in some outpatient cases where the type of malignancy and chemotherapy combination call for this, but it is not routine. One example where prophylaxis is recommended is for patients with multiple myeloma receiving thalidomide, lenalidomide or pomalidomide with chemotherapy and/or dexamethasone as their risk of VTE is high. Prophylactic options include aspirin, unfractionated heparin (though this cannot be administered in an outpatient setting), low molecular weight heparins (LMWH) (e.g. dalteparin, enoxaparin and fondaparinux). All of these agents are given at lower doses than the doses given for therapeutic treatment of an established VTE.

Treatment

The mainstay of VTE treatment in cancer patients is LMWH. Head to head trials have shown that it is more effective than warfarin at preventing recurrent cancer-associated thromboembolisms (CAT), and has a lower incidence of major bleeding. Some appropriate LMWHs include dalteparin, enoxaparin and tinzaparin. Some of the direct oral anticoagulants (DOAC) have shown to be non-inferior to LMWH for treating CAT, and may be implemented into practice in the near future as more data becomes available on the efficacy and safety of these agents (9, 10). Standard duration of treatment is 6 months, but this should be re-evaluated at least every 3 months and a discussion for extension of treatment in certain clinical situations where people are high risk of recurrence is warranted (e.g. patients who continue to live with incurable cancer).

1. Al-Samkari H, Connors JM. cancers The Role of Direct Oral Anticoagulants in Treatment of Cancer-Associated Thrombosis. [cited 2019 May 3]; Available from: www.mdpi.com/journal/cancers
2. Peterson E. Cancer Associated Thrombosis Review and Update. In: Family Practice Oncology CME Day [Internet]. 2015 [cited 2019 May 3]. Available from: http://www.bccancer.bc.ca/family-oncology-network-site/Documents/_07 Erica Peterson Thrombosis.pdf
3. Peterson E, Raziya M. Cancer Associated Thrombosis. In: GPO Case Study Day [Internet]. Vancouver; 2016 [cited 2019 May 3]. Available from: http://www.bccancer.bc.ca/family-oncology-network-site/Documents/02 Venous Thromboembolism - R. Mia, E. Peterson.pdf
4. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. 2008 [cited 2019 May 6]; Available from: www.bloodjournal.org
5. Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, et al. Excluding Pulmonary Embolism at the Bedside without Diagnostic Imaging: Management of Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a Simple Clinical Model and d -dimer. Ann Intern Med [Internet]. 2001 Jul 17 [cited 2019 May 6];135(2):98. Available from: http://annals.org/article.aspx?doi=10.7326/0003-4819-135-2-200107170-00010
6. Silveira PC, Ip IK, Goldhaber SZ, Piazza G, Benson CB, Khorasani R. Performance of Wells Score for Deep Vein Thrombosis in the Inpatient Setting. JAMA Intern Med [Internet]. 2015 Jul 1 [cited 2019 May 6];175(7):1112. Available from: http://archinte.jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2015.1687
7. Thompson BT, Kabrhel C. Overview of acute pulmonary embolism in adults - UpToDate [Internet]. 2019 [cited 2019 May 7]. Available from: https://www.uptodate.com/contents/overview-of-acute-pulmonary-embolism-in-adults?search=pulmonary embolism&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H13
8. Kearon C, Bauer K. Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity - UpToDate [Internet]. 2018 [cited 2019 May 7]. Available from: https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-deep-vein-thrombosis-of-the-lower-extremity?search=dvt clinical presentation&topicRef=1362&source=see_link
9. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med [Internet]. 2018 Feb 15;378(7):615–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29231094
10. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. JOURNAL OF CLINICAL ONCOLOGY Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol [Internet]. 2018;36:2017–23. Available from: https://doi.org/10.1200/JCO.2018.

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