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Venous Thromboembolism in the Cancer Population: Pathology, Risk, and Prevention

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Venous Thromboembolism in the Cancer Population: Pathology, Risk, and Prevention REVIEW Venous Thromboembolism in the Cancer Population: Pathology, Risk, and Prevention SUSAN HAWBAKER, MSN, APN, ANP-BC, OCN® From CNS Home Hospice and Pal- liative Care, Carol Stream, Illinois Abstract Author's disclosures of potential Patients with cancer have an increased risk of developing venous thrombo- conflicts of interest are found at embolism (VTE) and the incidence of these events has been increasing over the end of this article. the past decade. Venous thromboembolic events include both deep venous Correspondence to: Susan Haw- thrombosis and pulmonary embolism. These events contribute to higher baker, MSN, APN, ANP-BC, OCN®, morbidity and mortality rates. Understanding the complex pathogenesis of 1389 Crimson Lane, Yorkville, IL and risk factors for cancer-associated VTE will help guide advanced prac- 60560. E-mail: Susan.Hawbaker@ gmail.com titioners to improve outcomes with prophylaxis. The American Society of © 2012 Harborside Press® Clinical Oncology, the National Comprehensive Cancer Network, and the Eu- ropean Society of Medical Oncology have utilized this information and de- veloped evidence-based guidelines for prophylactic management for those who are at highest risk of developing cancer-associated VTE. This review will discuss the impact of cancer-associated VTE as well as its underlying pathogenesis, risk factors, and current recommendations for prophylaxis. J Adv Pract Oncol 2012;3:23–33 atients with cancer have a on mortality and morbidity in cancer two- to sixfold increase in has led to a need to understand the un- the risk of developing ve- derlying pathogenesis, risk factors, and nous thromboembolism possible prophylactic options available. P(VTEs; Samama, Dahl, Quinlan, Mis- Armand Trousseau first identified metti, & Rosencher, 2003), and the a relationship between cancer and co- incidence continues to increase with agulopathy in 1865 (Caine, Stonelake, cancer-associated VTE represent- Lip, & Kehoe, 2002). Due to the in- ing nearly 20% of all cases (Heit et al., creasing incidence and impact that 2002). These cases have shown to have VTE has on cancer, researchers con- a major impact on prognosis, mortality, tinue to expand on Trousseau’s dis- and morbidity of the cancer population. covery by exploring the complicated Not only does the incidence of VTE im- interactions between host cells, cancer pact prognosis, but it also deters and cells, and treatment regimens that un- complicates treatment options. This in- derlie the pathogenesis of coagulopa- creased awareness of the impact of VTE thy in malignancy. AdvancedPractitioner.com 23 Vol 3 . No 1 . Jan/Feb 2012 REVIEW HAWBAKER The purpose of this review is to discuss the Specific factors associated with an increase in epidemiology of VTE and malignancy, explore the incidence of VTE include time from diagnosis, ag- known hypercoagulable pathogenesis associated gressiveness of cancer, and metastatic involvement. with cancer VTE, understand the risk factors for The relative risk of developing VTE is seven times cancer-associated VTE, and outline the current higher in patients who have active cancer, with the recommendations and guidelines for prevention highest incidence rate occurring within the first of VTE in the oncology setting. few months after diagnosis (Wun & White, 2009). For example, the incidence rate in colon cancer is Epidemiology 5% in the first 6 months after diagnosis vs. 1.4% in The incidence of VTE in the cancer population the following 6 months (Wun & White, 2008). In has been increasing over the past decade; identi- addition, advanced cancers are associated with a fying the epidemiology of VTE in this population two to three times higher incidence of fatal VTE will help oncology advanced practitioners (APs) (Rodrigues, Ferrarotto, Filho, Novis, & Hoff, 2010). understand its prognosis, prophylaxis, and treat- Patients who have quick metastatic spread com- ment. Between 1980 and 2000 the incidence rates pared to a large extent of metastasis have a higher of VTE increased from 0.6% (Levitan et al., 1999) occurrence rate of VTE (Wun & White, 2009; Ro- to 4% (Khorana, Francis, Culakova, Kuderer, & Ly- driquez et al., 2007). man, 2007a; Stein et al., 2006), which represents Cancer-associated VTE is a leading cause of nearly a 400% increase. To determine possible morbidity and mortality in both ambulatory and causes for this increase, studies have examined the hospitalized patients (Wun & White, 2009; Khora- relationship among VTE incidence, cancer-related na et al., 2007b). Researchers have identified poor therapies, and diagnostic procedural usage. survival and prognosis in cancer patients with In the setting of cancer-related therapies, pa- VTE compared to cancer patients without VTE, tients receiving chemotherapy saw nearly a 50% with only 12% surviving past 1 year (Sorensen, increase in their incidence rates of VTE within Mellemkjaer, Olsen, & Baron, 2000). Both surgery the past decade (3.9% to 5.7%), whereas can- and chemotherapy have had a huge impact on the cer patients undergoing surgery experienced no mortality rates associated with VTE. Patients re- change (Khorana et al., 2007a). It has been specu- ceiving chemotherapy have a rate of VTE-related lated that the increase in the use of diagnostics death that is 47 times higher than that of the gen- has also had an impact on the overall increasing eral population (Khorana et al., 2007b). In addi- rate of cancer-associated VTE. However, studies tion, VTE is the most common cause of death after have found that the use of newer chemotherapeu- cancer-related surgery (Agnelli, Bolis, Capussotti, tic regimens as well as the use of high-resolution Scarpa, Tonelli, et al., 2006), with a death rate tri- computed tomography (CT) is likely the cause ple that of the noncancer surgical patient (Khosra- (Khorana et al., 2007a). The newer diagnostic vi-Shai & Perez-Manga, 2009). technology, such as high-resolution CT, provides better visualization, leading to an increase in VTE Pathogenesis findings. However, it has been estimated that the The pathogenesis of cancer-associated throm- actual incidence rate of VTE in the oncology pop- bosis is complicated and multifactorial. The basic ulation is underestimated, as postmortem studies pathology of thrombosis consists of Virchow’s triad: have found VTE in nearly 50% of all cancer pa- venous stasis, endothelial damage, and an intrinsic tients (Goldenberg, Kahn, & Solymoss, 2003). hypercoagulable state. This pathology continues in the oncology patient; however, it is the intrinsic hy- percoagulable state that exerts the most influence on this population’s elevated risk (Figure 1). The tumor cells themselves contribute to the Use your smartphone to access ASCO, ESMO, and NCCN intrinsic nature of clotting in the oncology popula- guidelines for the management tion. These cells do this with four different mech- of venous thromboembolism anisms of action (Table 1): (1) production of proco- SEE PAGE 21 agulant factors activating thrombosis formation, (2) release of fibrinolytic activities, (3) generation J Adv Pract Oncol 24 AdvancedPractitioner.com VENOUS THROMBOEMBOLISM IN THE CANCER POPULATION REVIEW Host cells Platelets Leukocytes Endothelial cell Tumor cell Cytokine Fibrinolytic activities activities Release of: Procoagulant Expression of: • IL-1ß activities • u-PA • TNF-α Production of: • t-PA • VEGF • PAI-1 • TF • PAI-2 • CP Thrombosis formation Figure 1. Pathogenesis of cancer-associated venous thromboembolism. Information from Caine et al. (2002), Falanga & Vignoli (2004), Gupta et al. (2005), Karimi & Cohan (2010), and Kuderer et al. (2009). IL-1ß = interleukin-1ß; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor; TF = tissue factor; CP = cancer procoagulant; u-PA = urokinase-type activator; t-PA = tissue-type plasminogen activator; PA-1 = plasminogen activator inhibitor-1; PAI-2 = plasminogen activator inhibitor-2. of acute phase reactants, including inflammatory 2009). Under normal circumstances, tissue factor cytokines that activate the clotting cascade, and is released in response to an inflammatory stimulus; (4) interaction with host blood cells (Caine et al., however, in malignant cells tissue factor is expressed 2002; Falanga & Vignoli, 2004; Gupta, Charan, & in a continuous and increasing manner, which con- Kumar, 2005; Karimi & Cohan, 2010). tributes to constant procoagulant activity (Caine et al., 2002; Rodrigues et al., 2010). PROCOAGULANT MECHANISMS Cancer procoagulant, found mainly in malig- Procoagulant activity refers to when cells pro- nant tissues, is a protease enzyme that activates mote the formation of fibrin deposits at injured ar- factor X of the coagulation pathway directly (Var- eas (Caine et al., 2002). The main procoagulants ex- ki, 2007). It is released by many different types of pressed in tumor cells are tissue factor and cancer tumor cells, and it actively promotes thrombosis procoagulant (Kuderer, Ortel, & Francis, 2009). and platelet activation (Karimi & Cohan, 2010). Tissue factor is a protein present on subendo- thelium, platelets, and leukocytes that forms a com- FIBRINOLYTIC MECHANISMS plex with factor VII (Kuderer et al., 2009; Rodrigues Tumor cells have the capacity to express all et al., 2010). This complex then activates factors IX the needed inhibitors and activators to regulate and X in the coagulation pathway (Kuderer et al., the fibrinolytic pathway (Caine et al., 2002). This AdvancedPractitioner.com 25 Vol 3 . No 1 . Jan/Feb 2012 REVIEW HAWBAKER Karimi & Cohan, 2010).
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