By David Altszuler, Class of 2012
Faculty Peer Reviewed
An empiric association between occult malignancy and thrombophlebitis has been recognized since Trousseau first reported the syndrome in 1865. The mechanism by which cancer predisposes to thrombophilia has not been fully elucidated; however, it is now clear that this is a symbiotic relationship. The second leading cause of death in hospitalized cancer patients (and a leading cause of death in ambulatory cancer patients) is venous thromboembolism. There are algorithms to identify cancer patients at high risk for developing venous thromboembolism (VTE), and a recently undertaken clinical trial exploring the efficacy of anticoagulation prophylaxis in these patients will likely establish guidelines for prophylactic treatment in the outpatient setting. There are patient-, tumor-, and treatment-related risk factors for development of VTE.[4,5] Cancer patients who develop a VTE should be treated with low-molecular-weight heparin, and all hospitalized cancer patients should have anticoagulation prophylaxis, especially if the patient is bedridden, scheduled to undergo major cancer surgery, or has a prior history of VTE.[6,7] An inferior vena cava filter should be considered for 1) patients who are currently bleeding or are at high risk for bleeding, 2) have recurrent VTE despite anticoagulation, 3) develop VTE immediately postoperatively, 4) present with a large primary or metastatic CNS tumor, 5) present with cor pulmonale, or 6) have a significant fall risk.
The aim of this paper is to explore the literature concerning anticoagulation as an adjunct cancer treatment, not just as a treatment of VTE. The interactions between components of the clotting cascade and tumor cells are still being explored, but it has become clear in the last few decades that platelets play a pivotal role in tumor growth, angiogenesis, metastasis, and escape from immune surveillance. It appears that one of the key regulators of this tumor-platelet interaction is thrombin. Most tumor cells have constitutively active tissue factor on their surface and thus are able to generate active thrombin in concentrations sufficient to overcome host antithrombin mechanisms.[9,10] Thrombin enhances the tumor cell-platelet interaction by activating the protease activated receptor-1 (PAR-1) on tumor cells, which allows tumor cell activation and subsequent avid binding to platelets, fibronectin, von Willebrand factor, and endothelial cells. Thrombin has also been shown to act as a tumor growth factor  as well as an inducer of metastasis.
Experiments conducted by Simon Karpatkin’s group demonstrated that inhibition of endogenous thrombin by pre-treatment with hirudin (a direct thrombin inhibitor, capable of neutralizing thrombin bound to the tumor-thrombus complex as well as in the plasma[14,15]) resulted in smaller tumor size and fewer metastases to the lungs in both murine and human (inoculated in nude mice) tumor models.[12,13]
Interestingly, two clinical studies have suggested a link between hypercoagulability and occult malignancy. One study followed 854 healthy patients with deep vein thrombosis; one group received warfarin for 6 weeks while the other group received warfarin for 6 months. The patients were followed for 6 years. It was noted that the group who received warfarin for only 6 weeks had a higher overall incidence of cancer (odds ratio 1.6, 95% CI 1.1-2.4, p=0.02) and a much higher incidence of urogenital cancer (odds ratio 2.56, 95% CI 1.3-5.0). A second study looked prospectively at increased mortality from myocardial infarction (MI) in otherwise healthy men who had a lab diagnosis of hypercoagulability. While no increased mortality was noted from MI, total cancer mortality in hypercoagulable patients was 11.3% vs 5.1%, relative risk 2.2 (p=0.015). These intriguing observational studies raise the question of whether adding an anticoagulant early in the treatment of solid tumors would provide a survival benefit.
As the intricacies of tumor biology are elucidated, it is becoming clear that platelets and clotting factors are closely linked with the growth, angiogenic potential, invasiveness, and the propensity for metastasis of solid tumors. In a 1968 study, Gasic and colleagues noted a survival benefit and decreased lung metastases in mice that were made thrombocytopenic prior to inoculation with tumor cells. Some studies of the efficacy of low-molecular-weight heparin (LMWH) in the treatment of malignancy-associated VTE have reported a survival benefit due not only to resolution of the thrombus but also due to an antitumor effect.[19-21] A few studies have been conducted in which patients were placed on LMWH as an adjunct therapy before VTE became clinically apparent.[22-26] In general, the results of these trials have been promising. One particular study, the CLOT trial, found that patients (with different kinds of solid tumors) randomized to the LMWH-plus-standard-of-care group had a statistically significant survival benefit compared to those who only received the standard-of-care chemotherapy and/or radiation therapy. However, the greatest survival benefit was seen in those patients without evident metastatic disease, who had better prognosis at the time of randomization.
Use of antiplatelet agents for cancer chemoprevention has garnered much attention recently and is an area of active research, with survival benefits demonstrated in colorectal cancer and lung cancer trials.[27, 28] However, a full discussion of the topic is beyond the scope of this article.
Thus, we are left without a satisfactory answer to the question of adjunct anticoagulation. LMWH is clearly indicated for any at-risk hospitalized patient with malignancy and is suggested for all hospitalized cancer patients. Anticoagulation is also indicated for all at-risk outpatients, namely those with prior VTE and those recovering from cancer surgery. The results of the studies indicate that patients demonstrate a survival benefit with LMWH, with the greatest benefit seen in patients treated early in disease progression; but these possible benefits must be weighed against the risks, costs, and inconvenience of chemopreventive anticoagulation.
By David Altszuler, 4th year medical student at NYU School of Medicine
Reviewed by Ahmed Sawas, MD, Division of Oncology, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
1. Trousseau A. Phlegmasia alba dolens. Clin Med Hotel-dieu Paris. 1865;3:654-712.
2. Nijziel MR, van Oerle R, Hillen HF, Hamulyák K. From Trousseau to angiogenesis: the link between the haemostatic system and cancer. Neth J Med. 2006;64(11):403-410.
3. Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009;27(29):4821-4826. http://jco.ascopubs.org/content/27/29/4821.full
4. Khorana AA, Liebman HA, White RH, et al. The risk of venous thromboembolism in patients with cancer. In: American Society of Clinical Oncology; ASCO Educational Book. Alexandria, VA;2008:240-248.
5. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model of chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. http://bloodjournal.hematologylibrary.org/content/111/10/4902.full.pdf
6. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25(34):5490-5505. http://jco.ascopubs.org/content/25/34/5490
7. Khorana AA. Cancer and thrombosis: implications of published guidelines for clinical practice. Ann Oncol. 2009;20(10):1619-1630.
8. Abdel-Razeq H, Mansour A, Ismael Y, Abdulelah H. Inferior vena cava filters in cancer patients: to filter or not to filter. Ther Clin Risk Manag. 2011;7:99-102. http://www.ncbi.nlm.nih.gov/pubmed/21479140
9. Nierodzik M, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo. J Clin Invest. 1991;87(1):229-236.
10. Grand RJA, Turnell AS, Grabham PW. Cellular consequences of thrombin-receptor activation. Biochem J. 1996;313(Pt 2):353-368.
11. Honn KV, Sloane BF, Cavanaugh PG. Role of the coagulation system in tumor-cell-induced platelet aggregation and metastasis. Haemostasis. 1988;18(1):37-46. http://www.ncbi.nlm.nih.gov/pubmed/3047022
12. Nierodzik M, Chen K, Takeshita K, et al. Protease activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood. 1998;92(10):3694-3700. http://bloodjournal.hematologylibrary.org/content/92/10/3694.full.pdf
13. Nierodzik M, Bain RM, Liu L-X, Shivji M, Takeshita K, Karpatkin S. Presence of the seven transmembrane thrombin receptor on human tumour cells: effect of activation on tumour adhesion to platelets and tumor tyrosine phosphorylation. Brit J Hematol. 1996;92(2):452-457.
14. Green D, Karpatkin S. Role of thrombin as a tumor growth factor. Cell Cycle. 2010;9(4):656-661.
15. Hu L, Lee M, Campbell W, Perez-Soler R, Karpatkin S. Role of endogenous thrombin in tumor implantation, seeding and spontaneous metastasis. Blood. 2004;104(9):2746-2751.
16. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. Duration of Anti-coagulation Trial. N Engl J Med. 2000;342(26):1953-1958. http://www.nejm.org/doi/full/10.1056/NEJM200006293422604
17. Miller GJ, Bauer KA, Howarth DJ, Cooper JA, Humphries SE, Rosenberg RD. Increased incidence of neoplasia of the digestive tract in men with persistent activation of the coagulant pathway. J Thromb Haemost. 2004;2(12):2107-2114. http://discovery.ucl.ac.uk/142619/
18. Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Pathol. 1968;61:46-53.
19. Lemoine NR. Antithrombotic therapy in cancer. J Clinic Oncol. 2005;23(10):2119-2120.
20. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J; ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006;12(4):389–396.
21. Robert F. The potential benefits of low-molecular-weight heparins in cancer patients. J Hematol Oncol. 2010:3:3.
22. Kakkar AK, Levine MN, Kadziola Z, et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004;22(10):1944-1948. http://www.moffitt.org/CCJRoot/v12s1/pdf/22.pdf
23. Altinbas M, Coskun HS, Er O, et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004;2(8):1266-1271.
24. Lee AYY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005; 23(10):2123-2129.
25. Klerk CPW, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005;23(10):2130-2135. http://jco.ascopubs.org/content/23/10/2130.full.pdf
26. Akl EA, van Doormaal FF, Barba M, et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev. 2007;(3);CD006652.
27. Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol. 2011;106(7):1340-1350.
28. Oh SW, Myung SK, Park JY, Lee CM, Kwon HT, Korean Meta-analysis (KORMA) Study Group. Aspirin use and risk for lung cancer: a meta-analysis. Ann Oncol. 2011 Mar 8 [epub ahead of print].