Japanese Journal of Clinical Oncology 31:388-394 (2001)
© 2001 Foundation for Promotion of Cancer Research
High Preoperative Plasma D-dimer Level is Associated with Advanced Tumor Stage and Short Survival After Curative Resection in Patients with Colorectal Cancer
Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Saitama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: An elevated plasma D-dimer level indicates activation of coagulation and fibrinolysis. Previous studies demonstrated that the preoperative plasma D-dimer level correlates with tumor stage in patients with colorectal cancer. This study examined the relationship between preoperative plasma D-dimer level and both pathological findings and TNM classification and examined the prognostic significance of preoperative plasma D-dimer level.
Methods: Preoperative plasma D-dimer levels were measured in 93 patients who underwent curative resection of colorectal cancer and 40 patients with benign colorectal diseases other than inflammatory bowel disease. The results were analyzed for correlations between preoperative plasma D-dimer levels in patients with colorectal cancer and pathological findings, TNM classification and postoperative survival.
Results: Preoperative plasma D-dimer levels were significantly higher in patients with colorectal cancer than in patients with benign colorectal diseases. Plasma D-dimer levels were higher in patients with tumors that were relatively large, had relatively deep wall penetration and were at a relatively advanced TNM stage. Higher preoperative plasma D-dimer levels were significantly associated with shorter postoperative overall survival. Results of analysis with a multivariate proportional hazard model suggested that preoperative plasma D-dimer level was the third strongest prognostic factor; exceeded in importance only by lymph node status and preoperative carcinoembryonic antigen level.
Conclusions: Elevated plasma D-dimer levels in patients with colorectal cancer are associated with relatively advanced tumor stage and short postoperative survival after curative resection. It appears that measurement of preoperative D-dimer level would be useful in the preoperative diagnosis of tumor stage and prediction of postoperative survival.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Activation of coagulation and fibrinolysis is known to be frequently associated with malignancy, although the mechanism involved has not been fully clarified. The extent of such activation has been reported to correlate with tumor stage and prognosis in some malignancies, including colorectal cancer (1–11).
D-dimer is a stable end-product of fibrin degradation and levels of D-dimer are elevated by enhanced fibrin formation and fibrinolysis (12). Edwards et al. reported that plasma D-dimer levels were elevated in patients with colorectal cancer, especially in patients with Dukes C tumors (13). We previously reported that preoperative plasma D-dimer levels were higher in patients with larger tumors and in patients with tumors exhibiting deeper wall penetration, lymph node metastasis, vascular invasion and hepatic metastasis, which indicate more advanced Dukes stages (14).
In the present study, we examined the association of preoperative plasma D-dimer level with pathological findings and tumor stage (TNM classification stage, which is also based on pathological findings), in patients who underwent curative resection of colorectal cancer. We also examined the prognostic significance of plasma D-dimer levels for postoperative survival.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Between May 1995 and December 1996, 145 patients underwent surgical resection of primary colorectal cancer at the Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine. Of those patients, 19 were preoperatively_excluded from the present study. Five were excluded for the following reasons: one patient who had been operated on for abdominal aortic aneurysm 1 month prior to the resection of rectal cancer; one patient who had been operated on for perforated rectal cancer; one patient with Child C liver cirrhosis; and two patients with advanced gastric cancers. Fourteen patients were excluded for miscellaneous reasons, such as failure to obtain consent for the study. Preoperative plasma D-dimer levels of the remaining 126 patients were measured. However, we postoperatively excluded 30 patients for whom the resection was non-curative owing to a positive surgical margin or distant metastasis. These 30 patients were excluded because the main purpose of the present study was to examine the relationship between preoperative plasma D-dimer levels and postoperative survival; also, after non-curative resection, the volume of the residual tumor (probably an important prognostic factor) could not be easily quantified. Another three patients who received 5-fluorouracil (5FU)-based intravenous chemotherapy in the immediate postoperative period were also excluded.
Thus, the study group comprised 93 patients who underwent curative resection of colorectal cancer. There were 62 men and 31 women. The mean age of the patients was 62.7 years, range 27–84 years. The tumor was located in the colon in 51 patients and in the rectum in 42 patients. Tumor pathology was diagnosed microscopically by examining hematoxylin–eosin-stained cut sections of the resected specimens. In patients with multiple primary tumors, the lesion which histology indicated was most advanced was used for analysis.
Tumor stages were evaluated according to the TNM classification (15). However, histological determination of TNM stage was impossible for 10 patients, because fewer than 12 of their lymph nodes were histologically examined for metastasis (pNx). Of the remaining 83 patients, seven were at stage 0, 10 were at stage I, 30 were at stage II and 36 were at stage III. Thirty-six patients were operated on by a specialist in colorectal surgery (M.O.) and the remaining 57 patients by non-specialist surgeons. Four patients received adjuvant radiotherapy (30–50 Gy to the whole pelvis) in the perioperative period. Thirty-eight patients received 5FU-based adjuvant oral chemotherapy, which was usually started at 4 weeks after resection and continued for at least 12 weeks.
In order to measure plasma D-dimer level and serum carcinoembryonic antigen (CEA) level, peripheral blood was obtained from the cubital vein within 3 days before the operation, after an overnight fast. The plasma levels of D-dimer were measured using a latex agglutination assay (LPIA-Ace, Dia-iatron, Tokyo, Japan). Because of the sensitivity of this assay, values below 0.06 µg/ml were set equal to 0.06 µg/ml. The measurement of plasma D-dimer level was repeated for 17 patients between 3 and 5 months after their operation. Serum CEA levels were measured with an enzyme immunoassay (Glaozyme, Wako, Osaka, Japan).
Comparisons between preoperative plasma D-dimer levels of different patient groups were performed using the non-parametric Mann–Whitney U-test or Kruskal–Wallis test. Tests for correlation between pairs of numerical variables were performed using the Spearman rank correlation test. Significance of changes in plasma D-dimer levels after operation was evaluated using the Wilcoxon signed rank test. A survey of patient survival was carried out at the end of November 2000 and the median length of time between surgery and the survey was 54.7 months. Results of this survey were analyzed using the Kaplan–Meier survival curves with the log-rank test and proportional hazard model. None of the 18 patients who were dead at the time of the survey were excluded; three patients had died of unrelated causes (sepsis after surgery for postoperative ileus, pneumonia and cerebral infarction). Values of p < 5% were considered statistically significant.
The reference group consisted of 40 patients with benign colorectal diseases other than inflammatory bowel disease, e.g. colorectal adenoma, irritable bowel syndrome and functional bowel disorder. Of these patients, 22 were male and 18 were female. Their mean age was 61.8 years, range 38–85 years. All the patients in the reference group were found to be negative for malignancy at the end of November 2000.
This study was approved by the review board of our hospital and written informed consent was obtained from all patients (those with colorectal cancer and those in the reference group).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Correlation Between Preoperative Plasma D-dimer Levels and Clinical Factors
Table 1 shows the distributions of preoperative plasma D-dimer levels in patients with colorectal cancer (patient group) and those in the reference group (who did not undergo surgery). The patient group had significantly higher plasma D-dimer levels than the reference group.
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Preoperative plasma D-dimer levels were significantly higher in elderly members of the patient group (r = 0.347, p < 0.001, Fig. 1). This correlation was also found in the reference group (r = 0.319, p = 0.042). Plasma D-dimer levels did not differ by gender.
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Correlation Between Preoperative Plasma D-dimer Levels and Pathological Findings of the Tumors (Table 2)
Plasma D-dimer levels did not differ between patients with colonic cancer and those with rectal cancer. However, plasma D-dimer levels were significantly higher in patients with moderately differentiated adenocarcinomas than in patients with cancer at other degrees of differentiation. In addition, patients with relatively large tumors, relatively deep wall penetration (larger pT value) and relatively advanced TNM stages had significantly higher preoperative plasma D-dimer levels. The presence of lymphatic invasion was marginally associated with higher preoperative D-dimer levels. By contrast, neither lymph node status (pN value) nor the presence of venous invasion correlated significantly with preoperative D-dimer levels.
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Relationship Between Preoperative Serum CEA Levels and Plasma D-dimer Levels
Preoperative plasma D-dimer levels did not correlate significantly with preoperative serum CEA levels in patients in the patient group (r = 0.162, p = 0.120).
Correlation Between Preoperative Plasma D-dimer Level and Postoperative Survival
Kaplan–Meier postoperative survival curves did not differ significantly between patients with high preoperative D-dimer levels (
0.50 µg/ml) and those with low levels (<0.50 µg/ml) (Fig. 2a). However, when the preoperative plasma D-dimer levels were graded into four classes according to the interquartile ranges, patients whose preoperative D-dimer levels were in the highest quartile (0.85 µg/ml) had significantly shorter postoperative survival than other patients (Fig. 2b).
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Survival Analysis Using Proportional Hazard Model
Table 3 summarizes the prognostic significance of preoperative plasma D-dimer levels, clinical factors, pathological findings and preoperative serum CEA levels, all analyzed using a univariate proportional hazard model. To obtain the normal distributions, plasma D-dimer levels and serum CEA levels were converted into logarithmic values which were then used in the analyses. The factors which were significantly associated with shorter postoperative survival in univariate analyses were the following: histological types other than well-differentiated adenocarcinoma; relatively large pT value; relatively large pN value; relatively advanced tumor stage; the presence of lymphatic invasion and venous invasion; relatively high preoperative plasma D-dimer level; and relatively high preoperative serum CEA level.
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Results of multivariate analysis using a proportional hazard model with backward elimination method are shown in Table 4. The results of this analysis indicated that the following were significant or nearly significant independent prognostic factors: extent of wall penetration (pT value); lymph node status (pN value); logarithm of preoperative plasma D-dimer level (Log D-dimer); and logarithm of preoperative serum CEA level (Log CEA). Further analysis showed that a model using pN value, Log D-dimer and Log CEA correlated most strongly with postoperative survival.
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Changes in Plasma D-dimer Levels After Operation
Postoperative plasma D-dimer levels of the 17 patients whose postoperative levels were measured were nearly significantly higher than those of the reference group [median (interquartile range) level of postoperative patients, 0.28 (0.10–0.58) µg/ml; median level of the reference group, 0.23 (0.09–0.49); p = 0.070]. Postoperative plasma D-dimer levels correlated significantly with preoperative plasma D-dimer levels (Fig. 3). However, changes in plasma D-dimer levels after operation were not significant. (p = 0.733).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, preoperative plasma D-dimer levels were significantly higher in patients with colorectal cancer which was curable by resection than in those with benign colorectal diseases. The preoperative plasma D-dimer level correlated with pathological findings of the tumors and TNM stage. Moreover, the postoperative survival of patients with higher preoperative plasma D-dimer levels was significantly shorter than that of patients with lower levels. These results suggest that measurement of preoperative plasma D-dimer level could be useful in the prediction of tumor stage and postoperative survival.
Plasma D-dimer level is reportedly elevated in patients with prostate cancer (1,7), colorectal cancer (2,4), lung cancer (2,3,8,10), cervical cancer of the uterus (5), ovarian malignancies (9,16) and breast cancer (11). Among patients with ovarian malignancies (9,16), colorectal cancer (13) and breast cancer (11), higher plasma D-dimer levels reportedly correlate with more advanced tumors. In our previous study of patients with colorectal cancer, including both those who underwent curative resection and those who underwent non-curative resection (14), preoperative plasma D-dimer levels were higher in patients with larger tumors, deeper wall penetration, lymph node metastasis and lymphatic and venous invasion. Levels were also higher in patients with hepatic metastasis and correlated significantly with preoperative serum CEA levels (14).
Since the main purpose of the present study was to examine the relationship between preoperative plasma D-dimer levels and postoperative survival, patients for whom resection was non-curative (such as those with stage IV tumors) were excluded. After non-curative resection, the volume of the residual tumor, which was probably an important prognostic factor, could not easily be quantified. In the present study, preoperative plasma D-dimer levels were significantly higher in patients with tumors exhibiting more advanced pathological characteristics and tumor stages. However, the exclusion of patients for whom resection was non-curative might have resulted in a failure to identify significant correlations between preoperative plasma D-dimer levels and lymph node metastasis, venous invasion and preoperative serum CEA levels.
Both univariate and multivariate analyses revealed that higher preoperative plasma D-dimer levels in patients with colorectal cancer were associated with shorter postoperative survival after curative resection. A similar relationship has been reported between preoperative plasma D-dimer levels and postoperative survival in patients with lung cancer (10). In contrast, pretreatment plasma D-dimer level is reportedly not an independent prognostic parameter in patients with ovarian cancer (17,18), probably because the plasma D-dimer level is altered by chemotherapy (17), sensitivity to which was an important prognostic factor. Since patients with colorectal cancer did not routinely receive intravenous adjuvant chemotherapy at our institution in 1995 and 1996, the three patients (of the original 145) who received intravenous adjuvant chemotherapy were excluded from the present study. However, the effects of intravenous adjuvant chemotherapy on plasma D-dimer level are being examined in our ongoing study.
It has been postulated that hypercoagulability associated with colorectal cancer is caused by both a tissue factor-dependent extrinsic pathway and a non-tissue-factor cancer procoagulant. The extrinsic pathway is thought to be initiated by a tissue factor produced by host mononuclear cells or host vascular endothelial cells (19,20). The non-tissue-factor cancer procoagulant (reportedly abundant in colorectal cancer tissue, where it is also reportedly produced) is thought to activate directly factor X (without involvement of factor VIIa) (21,22).
Activation of fibrinolysis by urokinase-type plasminogen activator (u-PA) is another characteristic of colorectal cancer (23–26). u-PA produced by tumor stroma cells binds to a u-PA receptor expressed on the surface of tumor cells (27). u-PA not only activates plasminogen (which degrades fibrin deposits that result from hypercoagulability) but also acts as a protease to disintegrate the matrix of the tumor–host interface (25). These biological activities of u-PA are considered to be important in both local tumor invasion and the establishment of distant metastasis (27).
In patients with colorectal cancer and those with benign colorectal diseases, preoperative plasma D-dimer levels were higher in the elderly. Elevated plasma D-dimer levels have reportedly been observed in healthy elderly subjects and are thought to be due to generalized enhancement of coagulation and fibrinolysis in the elderly (28,29). Increased plasma D-dimer levels are reportedly associated with a greater risk of arteriosclerotic diseases such as myocardial infarction and stroke (30,31). Plasma D-dimer levels in patients with colorectal cancer may be related not only to the biological nature of cancer but also to the background status of coagulation and fibrinolysis. If a patient has background hypercoagulability, he or she is likely to have an increased risk of diseases related to arteriosclerosis. Indeed, one of the three deaths in the present study which were unrelated to colorectal cancer was due to cerebral infarction in a patient with a stage II tumor associated with a high preoperative plasma D-dimer level (1.47 µg/ml).
Postoperative levels of plasma D-dimer were measured in only 17 patients. Therefore, the statistically insignificant change in plasma D-dimer levels after curative resection and the significant correlation between preoperative and postoperative plasma D-dimer levels should be considered preliminary. However, three important issues are raised by these results. First, the enhanced coagulation and fibrinolysis observed in patients with colorectal cancer may be systemic rather than localized at the site of the tumor. Second, the enhanced coagulation and fibrinolysis observed in patients with colorectal cancer may persist for some period of time after curative resection. Third, postoperative plasma D-dimer levels may also correlate with patients’ postoperative survival. To address these issues, measurement of plasma D-dimer levels before and after surgery is currently being conducted in a study at our hospital with a larger number of patients.
Measurement of plasma D-dimer levels using commercially available kits is neither complicated nor time consuming. If it is included in the routine preoperative laboratory examination of patients with colorectal cancer, it may provide supplementary information on tumor stage and prognosis. Although the number of patients in the present study was not large enough to establish the usefulness of the measurement of preoperative plasma D-dimer levels, it appears that further prospective studies with a larger number of patients would be worthwhile.
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FOOTNOTES |
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+ For reprints and all correspondence: Masatoshi Oya, Department of Surgery, Koshigaya Hospital, Dokkyo University School of Medicine, 2–1–50, Minami-Koshigaya, Koshigaya, Saitama 343-8555, Japan. E-mail: m-oya@dokkyomed.ac.jp
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Cooper DL, Sandler AB, Wilson LD, Duffy TP. Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer. Response to epsilon-aminocaproic acid. Cancer 1992;70:656–8.[Web of Science][Medline]
2 Wojtukiewicz MZ, Zacharski LR, Moritz TE, Hur K, Edwards RL, Rickles FR. Prognostic significance of blood coagulation tests in carcinoma of the lung and colon. Blood Coagul Fibrin 1992;3:429–37.[Web of Science][Medline]
3 Gabazza EC, Taguchi O, Yamakami T, Machishi M, Ibata H, Suzuki S. Evaluating prethrombotic state in lung cancer using molecular markers. Chest 1993;103:196–9.
4 van Duijnhoven EM, Lustermans FA, van Wersch JW. Evaluation of the coagulation/fibrionolysis balance in patients with colorectal cancer. Haemostasis 1993;23:168–72.[Web of Science][Medline]
5 Gadducci A, Baicchi U, Marrai R, Facchini V, del Bravo B, Fosella PV, et al. Pretreatment plasma levels of fibrinopeptide-A (FPA), D-dimer (DD) and von Willebrand factor (vWF) in patients with operable cervical cancer: influence of surgical–pathological stage, tumor size, histologic type and lymph node status. Gynecol Oncol 1993;49:354–8.[Web of Science][Medline]
6 Iversen LH, Okholm M, Thorlacius O. Pre- and postoperative state of coagulation and fibrinolysis in plasma of patients with benign and malignant colorectal disease. Thromb Haemost 1996;76:523–8.[Web of Science][Medline]
7 Geenen RW, Delaere KP, van Wersch JW. Coagulation and fibrinolysis activation markers in prostatic carcinoma patients. Eur J Clin Chem Clin Biochem 1997;35:69–72.[Web of Science][Medline]
8 Buccheri G, Ferrigno D, Ginardi C, Zuliani C. Haemostatic abnormalities in lung cancer: prognostic implications. Eur J Cancer 1997;33:50–5.
9 von Tempelhoff GF, Dietrich M, Niemann F, Schneider D, Hommel G, Heilmann L. Blood coagulation and thrombosis in patients with ovarian malignancy. Thromb Haemost 1997;77:456–61.[Web of Science][Medline]
10 Taguchi O, Gabazza EC, Yasue H, Kobayashi T, Yoshida M, Kobayashi H. Prognostic significance of plasma D-dimer levels in patients with lung cancer. Thorax 1997;52:563–5.[Abstract]
11 Blackwell K, Haroon Z, Broadwater G, Berry D, Harris L, Iglehart JD, et al. Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status. J Clin Oncol 2000;18:600–8.
12 Bick RL, Baker WF. Diagnostic efficacy of the D-dimer assay in disseminated intravascular coagulation (DIC). Thromb Res 1992;65:785–90.[Web of Science][Medline]
13 Edwards CM, Warren J, Armstrong L, Donnely PK. D-dimer: a useful marker of disease stage in surgery for colorectal cancer. Br J Surg 1993;80:1404–5.[Web of Science][Medline]
14 Oya M, Akiyama Y, Yanagida Y, Akao S, Ishikawa H. Plasma D-dimer level in patients with colorectal cancer: its role as a tumor marker. Surg Today 1998;28:373–8.[Web of Science][Medline]
15 American Joint Committee on Cancer. AJCC Cancer Staging Manual, 5th ed. Philadelphia: Lippincott-Raven 1997.
16 Rella C, Coviello M, Frenza ND, Falco G, Chiuri E, Colavito P, et al. Plasma D-dimer measurement as a marker of gynecological tumors: comparison with CA 125. Tumori 1993;79:347–51.[Web of Science][Medline]
17 Mirshahi SS, Pujade-Lauraine E, Soria C, Mirshahi M, Fretault J, Bernadou A, et al. D-dimer and CA 125 levels in patients with ovarian cancer during antineoplastic therapy. Cancer 1992;69:2289–92.[Web of Science][Medline]
18 Gadducci A, Marrai R, Baicchi U, Ferdeghini M, Fanucchi A, Weiss C, et al. Preoperative D-dimer plasma assay is not a predictor of clinical outcome for patients with advanced ovarian cancer. Gynecol Oncol 1997;66:85–8.[Web of Science][Medline]
19 Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995;346:1004–5.[Web of Science][Medline]
20 Costantini V, De Monte P, Cazzato AO, Stabile AM, Deveglia R, Frezzato E, et al. Systemic thrombin generation in cancer patients is correlated with extrinsic pathway activation. Blood Coagul Fibrin 1998;9:79–84.[Web of Science][Medline]
21 Francis JL, El-Baruni K, Roath OS, Taylor I. Factor X-activating activity in normal and malignant colorectal tissue. Thromb Res 1988;52:207–17.[Web of Science][Medline]
22 Gordon SG, Chelladurai M. Non-tissue factor procoagulants in cancer cells. Cancer Metastasis Rev 1992;11:267–82.[Web of Science][Medline]
23 Tissot J-D, Hauert J, Bachmann F. Characterization of plasminogen activators from normal human breast and colon and from breast and colon carcinomas. Int J Cancer 1984;34:295–302.[Web of Science][Medline]
24 Kirchhemer JC, Huber K, Wagner O, Binder BR. Patterns of fibrinolytic parameters in patients with gastrointestinal carcinomas. Br J Haematol 1987;66:85–9.[Web of Science][Medline]
25 Buo L, Lyberg T, Jorgensen L, Johansen HT, Aasen A. Location of plasminogen activator and PA inhibitor in human colorectal adenocarcinomas. APMIS 1993;101:235–41.[Web of Science][Medline]
26 Montemurro P, Conese M, Altomare DF, Memeo V, Colucci M, Semeraro N. Blood and tissue fibrinolytic profiles in patients with colorectal carcinoma. Int J Clin Lab Res 1995;25:195–200.[Web of Science][Medline]
27 Gandolfo GM, Conti L, Vercillo M. Fibrinolysis components as prognostic makers in breast cancer and colorectal carcinoma. Anticancer Res 1996;16:2155–60.[Web of Science][Medline]
28 Kario K, Matsuo T, Kobayashi H. Which factors affect high D-dimer levels in the elderly? Thromb Res 1991;62:501–8.[Web of Science][Medline]
29 Hager K, Platt D. Fibrin degeneration product concentrations (D-dimers) in the course of aging. Gerontology 1995;41:159–65.
30 Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998;19(Suppl C):C39–C43.
31 Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, Sharrett AR, et al. Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999;19:493–8.
Received December 27, 2000; accepted April 10, 2001.
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