Venous Thromboembolism
Background
Venous thromboembolism (VTE) is a known complication of patients with cancer. Approximately 15% of patients with cancer will develop a VTE. For some patients without cancer, a diagnosis of thrombosis may predict the development of a malignancy. Patients with VTE may also have reduced survival.1 Tumor type, individual chemotherapy agents, and placement of vascular access devices can contribute to the development of a deep vein thrombosis (DVT) . Some specific tumor types associated with DVT are brain tumors and gastrointestinal cancers, including CRC.2
Patients with a new VTE may describe swelling, tenderness, or warmth in the affected extremity. These complaints should prompt a physical exam and, if warranted, a Doppler or radiologic exam to confirm the presence of VTE. Shortness of breath, chest pain, or cough may indicate a pulmonary embolism (PE), and the exam to rule out this complication generally includes a radiologic scan, such as multislice computed tomographic pulmonary angiography.
Photo courtesy of Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP® Used with permission.
The risk factors for cancer-associated thrombus are multifactorial. Virchow’s triad (Figure 1) describes the components that play a role in the development of a thrombosis
- Hypercoagulability
- Vascular endothelial damage
- Stasis
Patients with cancer have activated coagulation systems and higher circulating levels of the physiologic initiator of blood coagulation, tissue factor (TF).3 The expression of TF by tumor or stromal cells promotes a procoagulant tumor microenvironment, with TF directly activating factor X. TF may also be released by monocytes or macrophages, inducing the activation of factor VII.4 TF also has a role in stimulation of angiogenesis; TF expression in cancer cells is associated with vascular endothelial growth factor and increased microvessel density,4 and high levels of TF have predicted poor prognosis in some cancers.5 Specific tumor types have been linked to higher risk of VTE, including breast, brain, and pancreatic tumors.6
Many patients with CRC receive chemotherapy, and some of these agents contribute to hypercoagulability (fluorouracil [5-FU], growth factors, and bevacizumab). These therapies can either directly or indirectly promote local activation of the coagulation process, injuring the vasculature.4 A significantly increased risk of VTE in patients undergoing chemotherapy was noted in a population-based case-control study.7 Newer therapies targeting angiogenesis, such as thalidomide and lenalidomide, in combination with steroids and other chemotherapeutic agents increase the risk of VTE. Higher risk of VTE has been reported in colon and gastric cancer patients receiving treatment with bevacizumab.8,9 Most CRCs are adenocarcinomas and, as such, contain mucin,10 which could contribute to hypercoagulability.
Additionally, many patients receive central catheters, which can increase the risk of thrombosis by contributing to vascular endothelial damage. The rates of VTE in patients with a central catheter range from 11.7% to 66% and are higher than rates associated with mechanical or septic catheter problems.11,12 The risk for catheter-associated thrombosis seems to peak within 4 to 8 weeks after placement of the catheter itself. Approximately one-third of patients with central catheter thrombosis have clinical symptoms.13
Lastly, many patients with CRC suffer from fatigue related to anemia and cancer therapy, which can contribute to vascular stasis if there is prolonged bed rest and immobilization. Nausea related to chemotherapy can lead to loss of appetite and dehydration. Without adequate fluid, there is electrolyte imbalance, concentration of chemotherapy leading to lack of strength and listlessness. Again, prolonged immobilization can predispose to vascular stasis and potentiate clot formation.2
Review of Literature
A retrospective analysis of all patients with CRC diagnosed in California during 1993-1995 and 1997-1999 showed that
- Of 68,142 patients diagnosed with the disease, the 2-year cumulative incidence of thrombosis was 3.1% (or 2,100 patients)14
- Approximately 5% of the patients developed VTE in the first 6 months after diagnosis, with a significantly decreased incidence rate after the first 6 months
- Metastatic disease and a higher number of chronic medical comorbidities were the most important predictors of VTE
- Almost one-third of the patients with incident VTE had reduced survival, leading the researchers to suspect that the presence of VTE might indicate a more biologically aggressive cancer
In a study of 193 patients with newly diagnosed CRC who were admitted for potentially curative surgery, compression ultrasonography was used postoperatively to detect the presence of DVT.1 Of these patients,
- 7.8% (15) had an existing DVT
- The rate was 16% in females versus 2.6% in males
- 1% had a pulmonary embolism (2 of 193)
The authors concluded that patients with CRC, especially women and those at higher risk, had a high preoperative prevalence of DVT.
The findings that patients with CRC who require chemotherapy and/or targeted agents agents are at higher risk for VTE have prompted further study. A recent report by Roddy et al15 discusses whether the incidence of thromboembolic events (arterial and venous) increases with the addition of bevacizumab to chemotherapy and erythropoietin-stimulating agents (ESAs).15 In a retrospective pilot study, 79 CRC patients were treated with either chemotherapy and bevacizumab, chemotherapy and ESA, or chemotherapy, bevacizumab, and ESA.15 The primary end point was the incidence of thromboembolic events. The study results showed the following:
Patient Group Incidence of VTE Events
Chemo + Bev
|
11%
|
Chemo + ESA
|
23.8%
|
Chemo + ESA + Bev
|
30%
|
The incidence of VTE was increased when chemotherapy was combined with the bevacizumab plus ESA versus with either agent alone. The median time to event was significantly shorter for the combination group versus the bevacizumab group. The authors cautioned that prior history of VTE, comorbid cardiac conditions, obesity, and exogenous hormone use should be considered when using the above treatment.15
Scappaticci and colleagues16 reported on the incidence of arterial or thromboembolic events during chemotherapy versus chemotherapy plus bevacizumab for a variety of cancer types and chemotherapy regimens. They concluded that the combination treatment was associated with an increased risk of arterial thromboembolism but not venous thromboembolism. Risk factors for an arterial thromboembolic event included a prior arterial thromboembolic event or age >65 years.
A recently published report examined the use of nadroparin for the prevention of VTE events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancers, including gastrointestinal tumors.17 This randomized, placebo-controlled, double-blind trial enrolled 1150 patients to receive either nadroparin at 3800 IU anti-Xa once a day (n = 779) or placebo (n = 387). The patients received the study treatment for the duration of chemotherapy up to a maximum of 4 months. Study results showed:
Group Developed VTE Developed Major Bleeding Event
Nadroparin
|
15/769 (2.0%)
|
5/769 (0.7%)
|
Placebo
|
15/381 (3.9%) P = 0.02
|
0/381 P = 0.18
|
Group Developed Minor Bleeding Event Serious Adverse Events
Nadroparin
|
57/769 (7.4%)
|
121 (15.7%)
|
Placebo
|
30/381 (7.9%)
|
67 (17.6%
|
The study authors concluded that the use of nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy, urging future studies to focus on high-risk patients for VTE.
Patients with CRC who received central venous catheters to facilitate the delivery of 5-FU chemotherapy were also found to have a higher risk of VTE.18 These patients (7 of 350 or 2%) developed VTE after placement of a central venous catheter. This prompted investigators to suggest thromboprophylaxis in patients with <span title="D-dimer—used to rule out DVT and often increased in individuals with VTE or PE. D-dimer molecules are released as the clot breaks down. A critical value is >= 0.51 mg/L
">D-dimers above 7.0 mcg/mL.
Because of the increased risk associated with surgery in CRC patients, clinicians should provide anticoagulant therapy, although the optimal thromboprophylactic dose is not yet known. Simonneau and colleagues19 investigated the benefits of nadroparin (2,850 IU) and enoxaparin (4,000 IU) SC for 9 + 2 days in a randomized, double-blind study in 950 evaluable patients undergoing CRC surgery. The VTE rate was 15.9% in the patients treated with nadroparin and 12.6% in the enoxaparin group, with comparable rates of proximal DVT between the 2 groups but a lower rate of symptomatic VTE in the patients receiving nadroparin. Less bleeding occurred with nadroparin, as well (7.3% vs 11.5%).
The benefits of sequential compression devices (SCDs) also contribute to prophylaxis treatment for high-risk colorectal surgery patients. Ramirez and colleagues20 searched a computerized database for information on patients with CRC or inflammatory bowel disease over a 7-year period. Patients who had major abdominal surgery and received SCD for VTE prophylaxis were identified. Of these patients, 1,281 were classified as highest risk using published parameters by the American Society of Colon and Rectal Surgeons, with an incidence of clinically detectable postoperative VTE of 0.78%. Prophylaxis for perioperative VTE with SCD was found to be a treatment option for patients at highest risk in this study. A Cochrane review confirmed that graduated compression stockings in combination with low-dose unfractionated heparin or low molecular weight heparin provide the optimal prophylaxis for this population of patients in the prevention of VTE.21
Treatment of VTE: Current Guidelines
Although guidelines have been in place for many years, consistent use of anticoagulant prophylaxis occurs in only about half of appropriate patients.22,23 The American Society of Clinical Oncology (ASCO), The National Comprehensive Cancer Network (NCCN), and The European Society for Medical Oncology (ESMO) have recently updated guidelines with specific approaches to the patient with cancer. In general, all 3 groups agree on the following:
- All hospitalized adults (medical or surgical) who have known or suspected cancer should be considered for VTE prophylaxis with anticoagulants (although ESMO restricts the recommendation to those who are bed bound)
- Cancer patients undergoing major cancer surgery should be anticoagulated; ESMO recommends prophylaxis with LMWH or UFH
- Patients with cancer and an established VTE should be anticoagulated to prevent recurrence of thromboembolic events
- Routine prophylaxis during outpatient chemotherapy is not indicated
Treatment of an established VTE in CRC is virtually the same as in most cancers and may include the use of heparin (either unfractionated or low molecular weight) and/or oral anticoagulants such as warfarin. Initial therapy should consist of LMWH or UFH for 5 to 10 days, followed by maintenance therapy with LMWH (= 6 months) to prevent recurrent VTE.4 Interesting data on prolongation of survival for patients with cancer when treated with LMWH therapy have been published, 3,24 LMWH helps prevent fatal VTE events, but its benefits seem to continue beyond active exposure.3
More research is needed to confirm that exposure to LMWH is associated with prolonged survival. The optimal duration of LMWH therapy is not known, as no study has examined its use beyond 6 months.25
For some patients unable to tolerate LMWH agents or heparin, the use of factor Xa antagonists may be appropriate.25 Placement of an inferior vena cava (IVC) filter may also be considered. Although there is no evidence of this intervention preventing a DVT, an IVC filter can help prevent a pulmonary embolism.26 Patients appropriate for an IVC filter should have either a lower-extremity DVT or a central or proximal DVT or PE, and be unable to be anticoagulated, nonadherent, or having pulmonary dysfunction, documented multiple PEs, or chronic pulmonary hypertension.26
Catheter-related thrombosis is treated medically or through removal of the catheter.13 Thrombolytic drugs, such as urokinase or recombinant tissue plasminogen activator (TPA), should be used within a 24-hour period for patients with clinical symptoms; chronic cases should receive LMWH, then oral anticoagulants or LMWH alone.13 There have been cautionary reports in the literature regarding the use of minidose warfarin in patients receiving FOLFOX (5-FU, leucovorin [LV], and oxaliplatin) or 5-FU/LV, because an elevation in the international normalized ratio (INR) may occur.27,28 Additionally, warnings exist for interactions with concomitant use of capecitabine and an oral coumarin-derivative anticoagulant; frequent monitoring of the INR is suggested, as postmarketing reports have shown significant increases in INR levels that were stabilized before initiation of capecitabine. Clinicians are urged to be aware of this potential drug interaction.
Suenaga and colleagues29 recently discussed management of VTE in CRC patients who received bevacizumab therapy. In a single-institution prospective cohort study, 41 patients were enrolled to determine the effectiveness of Doppler ultrasound imaging (DUS) in the early detection of catheter-related thrombosis to prevent severe VTE. The median duration of follow-up was 484 days, and curable symptomatic thrombosis occurred in 1 patient. Asymptomatic thrombosis occurred in 21 patients (51.2%). Thrombi remained without progression in 17 of the 21 patients who underwent re-evaluation, with enlargement of the thrombi noted in 4 patients. In 2 of the patients who had progression, pulmonary embolism (PE) occurred after the sixth cycle of therapy. The DUS allowed for early detection of asymptomatic thrombosis, and the authors suggest that careful follow-up and anticoagulant therapy as appropriate may be used without increased risk of bleeding. The results show that an enlarging thrombus or large thrombus (< 40mm in diameter) along with decreased venous flow is a risk factor for symptomatic thromboembolism or PE. The authors propose that routine prophylactic anticoagulant treatment should not be used in CRC patients treated with bevacizumab, as this agent can increase the risk of bleeding; therefore a noninvasive assessment technique, such as DUS, may be a useful strategy for determining early asymptomatic thrombi.29
Summary
There are a myriad of factors associated with VTE in patients with cancer, and VTE is the second most common cause of death for these patients.4 Patients with CRC have a higher risk for of VTE, and they benefit from anticoagulant prophylaxis with surgery. Postoperatively, chemotherapeutic treatments and placement of vascular access devices can increase their risk of VTE. Oncology nurses and clinicians caring for these patients should be aware of the risk for VTE and of signs and symptoms that may indicate the presence of a new thrombosis. Prompt recognition of VTE with appropriate anticoagulant therapy can help improve patient outcome.
Clinical Practice Guidelines
The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology version 1.2010 is available at: http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed April 8, 2010.
The American Society of Clinical Oncology (ASCO) Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer is available at: http://jco.ascopubs.org/cgi/reprint/JCO.2007.14.1283v1.pdf. Accessed April 8, 2010.
An algorithm, based on the ASCO Guideline, available as a patient tool, is located here. Assessed April 8, 2010.
References
-
Stender MT, Nielsen TS, Frokjaer JB, et al. High preoperative prevalence of deep venous thrombosis in patients with colorectal cancer. Br J Surg. 2007;94:1100-1103.
-
Viale PH, Schwartz RN. Venous thromboembolism in patients with cancer. Part I. Survey of oncology nurses’ attitudes and treatment practices for ambulatory settings. Clin
J Oncol Nurs. 2004;8:455-461.
-
Kakkar AK. Antithrombotic therapy and survival in cancer patients. Best Pract Res Clin Haematol. 2009;22:147-151.
-
Khorana AA. Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol. 2009;20:1619-1630. Full text at: http://annonc.oxfordjournals.org/cgi/content/full/20/10/1619. Accessed April 8, 2010.
-
Han LY, Landen CN Jr, Kamat AA, et al. Preoperative serum tissue factor levels are an independent prognostic factor in patients with ovarian carcinoma. J Clin Oncol. 2009;24:755-761.
-
Viale PH. Management of thromboembolism in the patient with cancer. Oncol Nurs Forum. 1999;26:1625-1632.
-
Heit JA, Silverstein MD, Mohl DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815.
-
Kabbinavar F, Hurwitz H, Fehrenbacher, L, et al. Phase III, randomized trial comparing bevacizumab plus fluorouracil (FU/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60-65.
-
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
-
Caine GJ, Stonelake PS, Lip GYH, Kehoe ST. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia. 2002;4:465-473.
-
Luciani A, Clement O, Halimi P, et al. Catheter-related upper extremity deep venous thrombosis in cancer patients: a prospective study based on Doppler US. Radiology. 2001;220:655-660.
-
De Cicco M, Matovic M, Balestreri L, et al. Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter: a prospective study. Thromb Res. 1997;86:101-113.
-
Gallieni M, Pittiruti M, Biffi R. Vascular access in oncology patients. CA Cancer J Clin. 2008;58:323-346.
-
Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2004;24:1112-1118.
-
Roddy JVF, Partridge SM, Rockey ML, et al. Thromboembolic events in patients with colorectal cancer receiving the combination of bevacizumab-based chemotherapy and erythropoietin stimulating agents. Am J Clin Oncol. 2009;July 31[Epub ahead of print]. http://journals.lww.com/amjclinicaloncology/pages/results.aspx?k=Roddy&Scope=AllIssues&txtKeywords=Roddy. Accessed April 8, 2010.
-
Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Can Inst. 2007;99:1232-1239. Full text at: http://jnci.oxfordjournals.org/cgi/reprint/99/16/1232. Accessed April 8, 2010.
-
Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009;10:943-949.
-
Yoshikawa R, Yanagi H, Noda M, et al. Venous thromboembolism in colorectal cancer patients with central venous catheters for 5-FU infusion-based pharmacokinetic modulating chemotherapy. Oncol Rep. 2005;13:627-632.
-
Simonneau G, Laporte S, Mismetti P, et al. A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaprin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. J Thromb Haemost. 2006;4:1693-1700.
-
Ramirez JI, Vassiliu P, Gonzalez-Ruiz C, et al. Sequential compression devices as prophylaxis for venous thrombosis in high-risk colorectal surgery patients: Reconsidering American Society of Colorectal Surgeons parameters. Am Surg. 2003;69:941-945.
-
Wille-Jorgensen P, Rasmussen MS, Andersen BR, Borly L. Heparins and mechanical methods for thromboprophylaxis in colorectal surgery. Cochrane Database Syst Rev. 2003;(4):CD001217.
-
Tapson, VF, Decousus, H, Pini M, et al, for the IMPROVE Investigators. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: Findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest. 2007;132:936-945.
-
Cohen AT, Tapson VF, Bergmann JF, et al. ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): A multinational cross-sectional study. Lancet. 2008;371:387-394.
-
Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of outpatients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:1-7.
-
Noble SIR, Shelley MD, Coles B, et al. Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9:577-584.
-
NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease—v.1.2010. http://www.nccn.org/professionals/physician_gls/PDF/vte.pdf. Accessed April 8, 2010.
-
Magagnoli M, Masci G, Carnaghi C, et al. Minidose warfarin is associated with a high incidence of International Normalized Ratio elevation during chemotherapy with FOLFOX regimen. Ann Oncol. 2003;14:959-960.
-
Brown MC. An adverse interaction between warfarin and 5-fluorouracil: a case report and review of the literature. Chemotherapy. 1999;45:392-395.
-
Suenaga M, Mizunuma N, Kobayashi K, et al. Management of venous thromboembolism in colorectal cancer patients treated with bevacizumab. Med Oncol. 2009; Aug 21 [Epub ahead of print]. Abstract at: http://www.springerlink.com/content/f242h11387346530/ Accessed April 8, 2010.
Key Definitions
adenocarcinomas—adeno means gland; carcinoma is a malignancy that begins in epithelial tissue accounting for 90%-95% of all CRC
arterial thromboembolism—a clot that forms in an artery. Sites could be cardiac and/or cerebral-related ischemia, infarctions with angina as a warning sign
compression ultrasonography—uses sound waves to visualize inside the leg. The patient lies supine, then prone as an ultrasound wand is applied to the leg. Considered the test of choice for suspected DVT
computed tomographic pulmonary angiography (CPTA)—effective method for diagnosing large pulmonary emboli; questionable for detecting small emboli
D-dimer—used to rule out DVT and often increased in individuals with VTE or PE. D-dimer molecules are released as the clot breaks down. A critical value is > 0.51 mg/L
deep vein thrombosis (DVT)—most commonly, a blood clot that forms in the deep veins of the leg; clots can form in the arms
Doppler ultrasound imaging (DUS)—measures movement using series of pulses to measure flow of blood
heparin (low molecular weight) (LMWH)—about 3,000 daltons; generally given once daily SC, not IM. Dosages in units and mg are not interchangeable.
mucin—an albumin-like substance found in mucous glands
sequential compression device (SCD)—alternating air current in a sleeve wrapped around the leg or arm to improve venous return and prevent stasis
thrombosis (deep vein) (DVT)—the formation a clot of coagulated blood attached at the site of its formation in a blood vessel. If the thrombosis impedes blood flow there may be death of tissue or infarction
thrombosis (prophylaxis)—usually heparins, to prevent clot formation in at-risk patients
thromboembolism (venous) (VTE)— a blood clot that forms in a vein
unfractionated heparin (UFH)—naturally occurring; molecular weight of ~20,000 to 30,000 daltons; often referred to as Standard Heparin
vascular endothelial damage—the flat cells that compose the inner lining of the entire circulatory system. They function to reduce friction, allowing blood to pass quickly and without trauma.
venous thromboembolism (VTE)—a blood clot that forms in a vein. Common sites are deep veins in the lower extremities and pelvis. Serious consequence is pulmonary embolism
Virchow’s triad—in 1856 Rudolf Virchow is credited with identifying factors that led to the development of thrombosis. The triad is thought to have come later as research confirmed and refined his findings.
|