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© 2003 American Society for Clinical Oncology Markers of Coagulation and Angiogenesis in Cancer-Associated Venous Thromboembolism
From the Departments of Internal Medicine and Pediatrics, University of South Florida, Tampa, FL; and the Department of Medicine and Center for Clinical Epidemiology and Community Studies, SMBD-Jewish General Hospital, and the Department of Hematology, Montreal General Hospital and St Mary’s Hospital, McGill University, Montreal, Quebec, Canada. Address reprint requests to Neil Goldenberg, MD, Department of Hematology, Oncology, and Bone Marrow Transplantation, The Children’s Hospital, 1056 E 19th Ave, B-115, Denver, CO 80218; e-mail: goldenberg.neil{at}tchden.org.
Purpose: We sought to determine whether venous thromboembolism in cancer patients is associated with aberrant plasma levels of hemostatic and angiogenic factors. Patients and Methods: Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVT; DVT + cancer group, n = 32), those without DVT (cancer control group, n = 36), and patients with acute DVT but no cancer (DVT control group, n = 58). Plasma assays of activation and inhibition of coagulation and fibrinolysis, as well as angiogenesis activation, were then performed. Results: Median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P = .0001 and P = .003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P < .0001 and P = .011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P < .0001, respectively). Median levels of tissue-type plasminogen activator were also significantly higher, while protein C activity was lower in the DVT + cancer group than in the DVT control group (14.6 ng/mL v 9.50 ng/mL, respectively, P = .0005; 0.89 U/mL v 1.11 U/mL, respectively, P = .0008). Conclusion: These data not only support prior observations of coagulation activation in patients with malignancy, but also provide new evidence for enhanced coagulation activation in the setting of acute venous thromboembolism in cancer. Future prospective studies are warranted to determine whether these and other potential markers of hypercoagulability may help to identify cancer patients at highest risk for venous thromboembolism.
THROMBOTIC EVENTS represent one of the most common complications, and a frequent cause of mortality, in patients with malignancy.1 Postmortem studies have revealed an incidence of thrombosis of nearly 50% in cancer patients.2 Indeed, it seems that venous thromboembolism may indicate a poor prognosis for patients with malignancy insofar as, in many instances, it signifies advanced disease.3 A greater appreciation of the impact of venous thromboembolism in cancer patients in recent years has led to several trials in which prophylactic anticoagulation was shown to be efficacious in select cancer groups,4–7 and perhaps even to confer some survival benefit.8–10 However, such trials have yielded no clear consensus as to the merits of routine anticoagulation in the general cancer population. Furthermore, although the association of a prothrombotic state with malignancy has been the subject of medical inquiry for more than a century (dating back to its recognition in 1865 by Trousseau11), the etiological mechanisms underlying this association are not well-understood. Among Virchow’s triad of venous stasis, endothelial damage, and an intrinsic hyperocagulable state, it is this latter component that has received the greatest focus in the study of venous thromboembolism in malignancy. With the evidence for an increased risk of venous thromboembolism provided by numerous trials in the late 1970s through early 1990s involving chemotherapy in cancer patients — in particular those with breast cancer12–17 — ardent efforts have been made in recent years to investigate hemostatic abnormalities in cancer patients that may contribute to their heightened risk of thrombosis. To date, in vitro studies have identified numerous procoagulant molecules produced by a variety of tumor types.18,19 Aberrancies in hemostatic parameters have been demonstrated in cancer patients in numerous studies utilizing classic indicators of coagulation and fibrinolysis, such as fibrinogen, tissue factor and factors of the coagulation cascade, protein C antigen or activity, plasminogen activators, plasminogen activator inhibitor-1, and fibrinogen degradation products, as well as newer-generation markers, including thrombin-antithrombin complex and prothrombin fragments 1 + 2.20–46 Although much variation is evident among these studies, in general, they support coagulation activation and often a low-grade disseminated intravascular coagulation that seems to be more prevalent in patients with advanced cancers than in those with more limited disease. Many such studies, however, have examined patients in the postoperative state or after recent administration of chemotherapy — both of which, as noted above, may be significant confounding factors with regard to hypercoagulability and venous thromboembolism in this patient population. Moreover, few studies have attempted to correlate hemostatic abnormalities with the clinical event of venous thromboembolism in cancer patients. In an effort to further elucidate the relationship between malignancy and hypercoagulability, as well as to better ascribe clinical significance to the hemostatic aberrations in cancer patients, we evaluated a number of sensitive markers of coagulation and fibrinolysis in cancer patients with acute deep venous thrombosis (DVT), in patients having acute DVT but no cancer, and in those with cancer but no thrombosis. In addition, given the endothelial alteration mediated by numerous tumor-associated angiogenic factors, we compared plasma levels of several angiogenic factors among these three patient groups to determine whether these factors may be implicated in the hypercoagulable state of malignancy.
Study Design All patients with objectively diagnosed, acute DVT at four McGill University hospitals between March 1998 and June 2000 were eligible for this study, which was approved by the ethics committee at each institution. Exclusion criteria for all groups were as follows: pre-existing diagnosis of inherited thrombophilia (patients were not screened by laboratory testing for inherited thrombophilia for the purposes of this study); known pregnancy; major surgery during the prior month; and chemotherapy during the preceding 2 weeks. Eligible patients to whom no exclusion criteria applied and who gave informed consent were sequentially enrolled in the study, and their blood samples were collected, as described later in this section, before initiation of any anticoagulant therapy. Patients with symptomatic acute DVT demonstrated by venous compression ultrasound with duplex Doppler were enrolled consecutively from emergency departments, vascular ultrasound departments, and inpatient hematology-oncology wards, and stratified into two groups for analysis according to the presence (DVT + cancer group) or absence (DVT control group) of known malignancy. Notably, patients diagnosed with a new malignancy during evaluation and treatment for acute thromboembolism were assigned to the DVT + cancer group; the decision to investigate for occult malignancy remained that of the treating physician and not of the study investigators. A third patient group consisted of patients with known cancer but no acute DVT (cancer control group) who met none of the aforementioned exclusion criteria, and were consecutively enrolled from outpatient hematology-oncology clinics and inpatient hematology-oncology wards at these hospitals during the same period.
Patient medical records were reviewed for collection of the following clinical data: age; sex; prior DVT; current smoking; current estrogen use (eg, hormone-replacement therapy, oral contraceptive pill); current biochemical evidence of hepatic or renal dysfunction (transaminase levels, or blood urea nitrogen and creatinine levels, respectively, For the laboratory studies, 10 mL of venous blood were collected by atraumatic antecubital venipuncture, with minimal applied stasis, into siliconized glass tubes containing 3.8% sodium citrate and transported in an ice-water bath. Platelet-free plasma was obtained by centrifugation at 3000 rpm for 10 minutes within 30 minutes of blood collection, followed by recentrifugation of the supernatant fraction at 3000 rpm for an additional 10 minutes. Plasma aliquots were kept at -70°C until testing. Assays were performed at the end of the study period by technicians in the Coagulation Laboratory of the Montreal General Hospital who were blinded to patient diagnoses and clinical characteristics. Fibrinogen was quantitated by the standard method of Clauss, and protein C activity was measured by clotting assay (Stago Diagnostica, Paris, France). The following tests were performed by enzyme-linked immunosorbent assay using commercially available kits: thrombin-antithrombin complex and prothrombin fragment 1 + 2 (Dade Behring, Auckland, New Zealand); von Willebrand factor (Stago Diagnostica); soluble tissue factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (American Diagnostica, Greenwich, CT); and vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor alpha-beta (R&D Systems, Minneapolis, MN). All assays were performed in accordance with manufacturer specifications.
Statistical Analysis For all tests, a P value of .05 or less was considered statistically significant. Of note, after examination of the raw data and before analysis, the complete data of two patients (one in the DVT + cancer group and one in the DVT control group) were excluded given extreme outlying values that were biologically implausible and likely due to in vitro artifact; accordingly, these two patients were not considered further in the analyses.
The clinical data obtained by medical record review are shown in Table 1  , with the distribution of cancer types in each group given in Table 2. There were 32 patients in the DVT + cancer group, 36 in the cancer control group, and 58 in the DVT control group. As indicated in Table 1, no significant differences were apparent among groups with respect to age, prior DVT, and biochemical evidence of renal or hepatic dysfunction. By contrast, the percentages of patients using exogenous estrogen and currently smoking were significantly different in the DVT + cancer group than the DVT control group (0% v 29% and 28% v 7.1%; P = .010 and P = .021; respectively). In addition, the proportion of males was significantly greater in the DVT + cancer group than in the cancer control group (72% v 28%; P = .001), as were the percentages of current smokers and patients with metastatic disease (28% v 5% and 63% v 24%; P = .045 and P = .002; respectively). However, further analysis demonstrated that no statistically significant differences in marker levels existed between those cancer patients who did, and those who did not, have metastatic disease (data not shown). As depicted in Table 2, a wide range of cancer types was represented. Although the distribution of cancers (with respect to the broad categories of hematologic, breast, lung, gastrointestinal, genitourinary, and other cancers) between the DVT + cancer and cancer control groups differed somewhat, none of the differences were statistically significant.
In Table 3 , laboratory results for each study group are presented. No significant differences in median plasma levels of fibrinogen, plasminogen activator inhibitor-1, tissue factor, vascular endothelial growth factor, platelet-derived growth factor alpha-beta, and basic fibroblast growth factor were detected among the study groups. However, median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P < .0001 and P = .003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P = .0001 and P < .011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P < .0001, respectively). In addition, median plasma levels of protein C activity were lower, while those of tissue-type plasminogen activator were higher, in the DVT + cancer group compared with the DVT control group (0.89 U/mL v 1.11 U/mL, respectively, P = .0008; 14.6 ng/mL v 9.50 ng/mL, P = .0005).
Our findings of increased plasma levels of thrombin-antithrombin complex and prothrombin fragments 1 + 2 along with decreased protein C activity support prior observations of generalized coagulation activation in cancer patients, and newly demonstrate the importance of coagulation activation in cancer-associated acute venous thromboembolism. Few previous studies have attempted to correlate the hemostatic abnormalities in cancer patients with the clinical event of venous thromboembolism, and only one such study was designed to exclude the potential confounder of a postoperative state.38 In that study, Johnson et al found no hemostatic differences between patients with or without DVT, with the exception that fibrinogen levels were significantly lower among those with DVT, as compared with those without DVT. However, these were hospice patients with advanced cancers, and hence, the results may not be representative of the general cancer population; moreover, the results may have been confounded by concurrent anticoagulant therapy. Importantly, with the exception of a small study by Falanga et al,46 in which preoperative thrombin-antithrombin complex levels correlated with risk of postoperative deep venous thrombosis in cancer patients, the extensive study of hypercoagulability in malignancy has not, to our knowledge to date, successfully demonstrated a specific coagulation abnormality in cancer patients to be predictive of venous thromboembolism, nor of response to anticoagulant prophylaxis or therapy.47 In addition to elevations in sensitive markers of the coagulation activation pathway, our results demonstrate increased von Willebrand factor antigen levels in cancer-associated acute venous thromboembolism. We found elevated von Willebrand factor levels among cancer patients with, versus without, acute thrombosis, suggesting that von Willebrand factor may be a marker for, or pathogenic in, the development of acute venous thromboembolism in patients with malignancy. Our findings with regard to von Willebrand factor support those of other studies demonstrating elevated plasma levels in patients with carcinomata of the prostate, bladder, ovary, or cervix; Kaposi’s sarcoma; head and neck tumors; and various disseminated malignancies.42,43,48–53 However, von Willebrand factor has rarely been evaluated in the context of venous thromboembolism,54,55 and the present study provides new evidence associating elevated von Willebrand factor levels with an acute thromboembolic event in cancer patients. Increases in von Willebrand factor antigen levels may be observed in a variety of inflammatory conditions; while a medical history of rheumatologic or autoimmune disease was not specifically ascertained in the study, it is worthy to note that none of the patients were brought to medical attention for such disorders at the time of enrollment. Von Willebrand factor is a larger multimeric glycoprotein that is known to function physiologically as a carrier for factor VIII and as a mediator of platelet adhesion to the endothelium. With the recent evidence that patients with disseminated malignancies, when compared with those with localized tumors, demonstrate both a significant increase in aberrant von Willebrand factor multimers and a deficiency of von Willebrand factor-cleaving protease,56 it can be hypothesized that abnormal von Willebrand factor multimers may play a pathogenic role in disrupting endothelial homeostasis toward a simultaneously pro-angiogenic and prothrombotic state. In this way, von Willebrand factor may in the future be implicated not only in tumor progression, but also in cancer-associated thrombogenesis. The demonstration of abnormal von Willebrand factor multimers and deficient levels of von Willebrand factor-cleaving protease in future studies of cancer patients with venous thromboembolism would lend support to such a hypothesis. In addition to its demonstration of increased coagulation activation and elevated von Willebrand factor levels in cancer-associated venous thromboembolism, the present study is important for its evaluation of angiogenic factors in this context. Angiogenic factors have long been implicated in the metastatic process through early work in vitro in which their effects on basement membrane proteolysis and endothelial cell motility and proliferation were demonstrated.57–60 Although a variety of angiogenic factors have been examined in patients with malignancy (with particular recent emphasis on vascular endothelial growth factor), no published studies have evaluated these molecules in cancer patients with venous thromboembolism. While no significant intergroup differences in angiogenic factor levels were detected in this study, a trend toward increased vascular endothelial growth factor levels in cancer patients with DVT was noted, and further investigation of the role of angiogenic factors in the hypercoagulable state of malignancy may be of interest. Despite our findings, it is doubtful at this time that one can distinguish those patients with malignancy who are at greatest risk for venous thromboembolism by using any one of these hemostatic or angiogenic markers individually. Instead, a combination of these markers may, in the future, prove useful in this regard. Further basic research coupled with well-controlled, longitudinal, prospective clinical studies will enable greater elucidation of the hypercoagulable state of malignancy, and may ultimately lead to the development of rational therapeutic approaches that, through a common mechanism, target both tumor progression and thrombosis.
The authors indicated no potential conflicts of interest.
We thank the following individuals for the contribution of their expertise: Carla Strulovitch, Marie Therese Nguyen, MD, Mark Agulnik, MD, Mavis Lipman, Jenny Kwan, Ghada Ameen, MD, Kim Nguyen, and Laurent Azoulay. We also wish to acknowledge the emergentologists, ematologists/oncologists, and ultrasound technicians at the McGill University hospitals for their support of the study.
Supported in part by an unrestricted research grant from Pharmacia and Upjohn.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2x the upper limit of normal values); cancer type; and presence of documented metastatic disease. 
2 analysis, or Fisher’s exact test, as appropriate, to detect differences between the DVT + cancer group and each of the control groups. In the primary analysis, laboratory data were found to be nonparametric and were hence analyzed by determining median values for each group; the Mann-Whitney test was then used to detect significant differences in median values between the DVT + cancer group and each of the control groups. In addition, the Mann-Whitney test was used to compare median laboratory values between cancer patients with and without metastatic disease to assess whether intergroup differences in the representation of patients metastatic disease may have affected the results. 
