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Cancer and Hypercoagulation: A Naturopathic Approach
How One Doctor Keeps Fibrinogen Levels Low in his Cancer Patients
Q&A With Naturopath Physician James Belanger, of Lexington Natural Health Center
Focus: You are a naturopath focusing almost exclusively on cancer patients for the last eleven years. How did this come about?
Belanger: I had testicular cancer—which is supposedly a “good” cancer to have because it is often treatable. I had several surgeries and they said keep coming back to be monitored with catscans and checkups, but if the cancer recurred I’d have to undergo chemotherapy. I certainly didn’t want to do that and I knew that it can take a while before a recurrence actually shows up on tests. All kinds of bodily processes precede visible cancer growth—such as activation of the clotting cascade that allows angiogenesis and blood vessel growth. And so in working to keep myself healthy and free of any recurrences, I became more and more interested in helping others as well.
Focus: Tell us about how you approach hypercoagulation and cancer.
Belanger: When I first see a cancer patient, I do a series of blood tests to look for growth factors in their blood that can influence the cancer. It is well documented in the scientific and clinical literature that cancer patients often have issues with hypercoagulation and even with excessive risk of blood clots. (See insert below: Hypercoagulation And Cancer). One important test measures fibrinogen levels in the blood.
Focus: Why is fibrinogen so important?
Belanger: Fibrinogen is a protein made in the liver that plays a key role in blood clotting. Fibrinogen is a sticky, fibrous coagulant in the blood, and there is a whole array of studies linking fibrinogen and hypercoagulation with the spread of cancer. Fibrinogen can raise the risk of tumor recurrence in several ways.
First, research shows that cancer cells can produce extra fibrinogen on their own. Second, when immune cells like macrophages infiltrate tumors to try and destroy them, the excess inflammation can cause the liver to make even more fibrinogen. So what does cancer do with all this extra fibrinogen? It uses it to grab hold of growth factors in the blood, like VEG-F and FGF, to help make blood vessels.
In addition, when there is excess fibrinogen in the bloodstream, red blood cells tend to aggregate in the tiny capillaries, creating areas of low oxygen tension (hypoxia). The hypoxia stimulates the tumors to produce even more blood vessels, increasing the aggressiveness of the cancer.
So in general, fibrinogen helps enhance the metastasis of cancer. We know that fibrinogen is very useful in wound healing, and they say cancer is like a wound that doesn’t heal. Cancer and its surrounding tissues produce the same kind of inflammatory cytokines as a wound. These inflammatory cytokines attract macrophages, and stimulate the production and binding of fibrinogen. A wound uses the fibrinogen to bind VEGF and other angiogenic growth factors to help make blood vessels to heal the tissue. Cancer uses the angiogenic growth factors bound by the fibrinogen to grow and metastasize.
Focus: So if you know that is cancer’s strategy, how do you thwart it?
Belanger: I measure fibrinogen levels and I put my patients who come back with high levels of fibrinogen on an enzyme complex called Lumbrokinase.
Focus: What levels of fibrinogen do you consider too high?
Belanger: There was a really nice study in early stage stomach cancer that looked at the five-year survival rate and measured fibrinogen levels before surgery. The patients that had fibrinogen levels between 180 and 310 had a longer five-year survival rate than those whose levels were over 310. And most labs say that 180 to 350 is normal and healthy. However, based on this study, if a cancer patient has fibrinogen levels over 310, I try to bring it down.
Focus: What is the highest fibrinogen level you’ve seen in a patient?
Belanger: I actually have seen levels as high as 900 in some patients. There are certain cancers, such as pancreatic, colon and prostate cancer, where you can almost guarantee that fibrinogen levels will be high. I wish there were already a study that showed you can keep cancer patients in remission longer, or prolong life in and of itself, by lowering fibrinogen levels. I hope to publish my own data at some point, but all I can say right now is that I think it’s a very important component to measure and address in every cancer patient.
Focus: What amount of lumbrokinase do you prescribe to your patients?
Belanger: The dose depends on the level of fibrinogen they are starting out with. In a patient with a very high level of 900, I will start them on 80 milligrams of lumbrokinase three times a day. If that only brings down their levels by, say, a few hundred points I will add other supplements like resveratrol and indole-3-carbinol to bring it down more. I will also measure interleukin-6 in the serum and use supplements like Tauroxicum if the patient’s level is over 4 pg/ml. Interleukin-6 is a potent inducer of fibrinogen synthesis in the liver. I have been experimenting with layering different supplements. Once a patient is down to a safe level I keep them at that dose and keep rechecking their levels.
Focus: Has anybody ever dropped too low?
Belanger: Occasionally I’ve seen someone drop to say, 150, when normal is 180 and then I decrease their supplements. Nobody has had any bleeding issues. I want to add something else about hypoxia that I didn’t mention before. There are studies showing that tissue hypoxia decreases the effectiveness of radiation. Radiation needs oxygen molecules in order to work, it turns them into free radicals which destroy the cancer cells. So cancer cells in tumor areas that are hypoxic are going to be more resistant to radiation treatment. So that’s another reason you want to lower fibrinogen levels. I look at lumbrokinase as a useful agent to help radiation work better. Even with chemotherapy, if the patient suffers from hypercoagulation that could impair effectiveness.
Focus: Can you summarize your overall approach?
Belanger: Well, I’ve been at this for eleven years, and over that time I’ve become more successful. I’ve found out what works and what doesn’t and I’ve found that each person is different. The same supplements don’t have the same effect in each person. And I’ve discovered that certain supplements don’t seem to mesh well. For instance, I don’t know why but when I gave curcumin with R-lipoic acid, it didn’t work anymore on inhibiting Interleukin 8 (another growth factor that I track).
In general, when I am able to improve various markers such as fibrinogen levels, my patients tend to report that their tumor has shrunk, or that—if they’re in remission already—they have not had a recurrence. And conversely, when the markers are high, I do see more recurrences. I also look at levels of fibrin breakdown products, such as D-dimer. I add bromelain if a patient has a high level of fibrin breakdown products. When I use lumbrokinase and bromelain together, I will see D-dimer levels start to fall. I use resveratrol because I’ve seen that in menopause women’s fibrinogen levels will go up, and so it seems that estrogen has an effect on fibrinogen. Resveratrol is a phytoestrogen. Basically, I’m trying to help my patients “beat” the catscan, trying to lower their risk level before something actually shows up.
Hypercoagulation and Cancer: A Look at the Latest Research
The body’s coagulation mechanisms may play a part in the development and spread of some cancers, according to recent research. Fibrin, for instance, promotes the growth of tumors and usually surrounds malignant tumors, while fibrinogen allows tumors to acquire growth factors.
For years, medical researchers have noticed that the presence of blood clots may be a prelude to cancer, and in one Swedish study in 2000, men taking anticoagulants such as heparin seemed to be protected against developing prostate cancer. In fact, in an article from the Albany College of Pharmacy published in 2006, it was noted that “the coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types…and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state.” And in a previous 2004 article from the same laboratory, published in Cardiovascular Drug Review, it was found that “Unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis.”
Hypercoagulation contributes to a significant percentage of mortality and morbidity in cancer patients, according to an article in Neoplasia in 2002. “Prothrombotic factors in cancer include the ability of tumor cells to produce and secrete procoagulant/fibrinolytic substances and inflammatory cytokines...” the researchers report. “Other mechanisms of thrombus promotion in malignancy include nonspecific factors such as the generation of acute phase reactants and necrosis (i.e., inflammation), abnormal protein metabolism (i.e., paraproteinemia), and hemodynamic compromise (i.e., stasis). In addition, anticancer therapy (i.e., surgery/chemotherapy/hormone therapy) may significantly increase the risk of thromboembolic events by similar mechanisms, e.g., procoagulant release, endothelial damage, or stimulation of tissue factor production by host cells.”
A 2008 study by researchers in South Korea found that blood levels of coagulation markers such as prothrombin fragment F1+2 and D-dimer, and prothrombin time (PT), correlated with the clinical stage and lymph node metastasis of patients with operable gastric cancer. A total of 110 patients were studied. Plasma D-dimer and PT were highly correlated with the clinical stage of the cancer. Similarly, PT and F1+2 levels were significant in predicting the presence of lymph node involvement.
In a previous 2006 study at the University of Tokyo, excess levels of fibrinogen were associated with a worse clinical outcome in stomach cancer. A total of 405 patients with gastric cancer who underwent surgery were evaluated. There was a positive correlation between plasma fibrinogen levels and the depth of invasion of tumors. Lymph node and liver metastasis were also positively correlated with excess fibrinogen levels. The researchers concluded that “hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome.” This research built on work from the University of Tokyo in 2005 that suggested that excess fibrinogen “may provide favorable circumstances for cancer cells to metastasize via the lymphatic system.”
A 2007 study of 105 patients with squamous cell cancer of the esophagus found that pretreatment levels of fibrinogen were correlated with prognosis. Researchers found that the plasma fibrinogen concentration (PFC) correlated significantly with the depth of invasion and with lymph node and distant organ metastasis. Patients with a higher fibrinogen level experienced a significantly worse overall survival.
Finally, a 2004 study from the National Cancer Center in Korea studied preoperative plasminogen levels in 354 stomach cancer patients undergoing surgery. “The plasma fibrinogen level was significantly lower in patients with early gastric cancer than in those with advanced gastric cancer…a significant relationship existed between the preoperative fibrinogen levels and the presence of metastatic lymph nodes and distant metastasis,” the researchers concluded. Once again, “these data suggest that the plasma fibrinogen level is a clinically important and useful marker of the extent of tumor progression in gastric cancer.”
What can we conclude? Fibrinogen levels are indeed an important marker in cancer and safely lowering fibrinogen may be useful.
—— Abstracts ——
J Gastroenterol Hepatol. 2007 Dec;22(12):2222-7. Pretreatment plasma fibrinogen level correlates with tumor progression and metastasis in patients with squamous cell carcinoma of the esophagus. Takeuchi H, Ikeuchi S, Kitagawa Y, Shimada A, Oishi T, Isobe Y, Kubochi K, Kitajima M, Matsumoto S.
BACKGROUND: Hypercoagulation has been reported to be associated with tumor progression and a poor prognosis in various carcinomas. In this study, we examined fibrinogen levels in pretreated patients with esophageal squamous cell carcinoma (ESCC) and assessed its correlation with clinicopathological factors and prognosis in patients with ESCC. METHODS: Pretreatment fibrinogen levels were examined prior to surgery or other treatments (e.g. endoscopic mucosal resection and chemoradiotherapy [CRT]) in 105 patients with primary ESCC. We investigated the association of fibrinogen levels with clinicopathological background factors and the survival of ESCC patients. RESULTS: The plasma fibrinogen concentration (PFC) ranged from 209.4 to 781.6 mg/dL. Pretreatment PFC correlated significantly with the depth of invasion (T factor). There also existed a significant correlation between higher fibrinogen levels and lymph node metastasis (N factor) and distant organ metastasis. Patients with a higher fibrinogen level experienced a significantly worse overall survival (P = 0.006). Fibrinogen levels strongly correlated with platelet counts, white blood cell counts and tumor length. Pretreatment PFC were observed to have a significant correlation with CRT responsiveness in ESCC patients in stages II and III (P = 0.005). CONCLUSION: This study revealed that higher levels of fibrinogen correlated with tumor progression, metastasis and poor responsiveness to CRT in ESCC patients.
Jpn J Clin Oncol. 2008 Jan;38(1):2-7. Plasma levels of prothrombin fragment F1+2, D-dimer and prothrombin time correlate with clinical stage and lymph node metastasis in operable gastric cancer patients. Kwon HC, Oh SY, Lee S, Kim SH, Han JY, Koh RY, Kim MC, Kim HJ.
OBJECTIVE: The principal objective of this study was to determine the relationship between preoperative coagulation tests and the extent of tumor involvement in gastric cancer patients. METHOD: A total of 110 patients with adenocarcinoma of the stomach were studied in order to evaluate this relationship. Platelet count (P), prothrombin time (PT), activated partial thromboplastin time, D-dimer, fibrinogen degradation product, thrombin-antithrombin complex and prothrombin fragment F1+2 (F1+2) were evaluated. RESULTS: The D-dimer levels were positively correlated with the depth of invasion (P =0.007). Plasma D-dimer and PT were highly correlated with degree of lymph node involvement (P = 0.006, 0.004, respectively). D-dimer level, PT and plasma F1+2 level were correlated with clinical stage (P = 0.001, 0.017, 0.031, respectively). PT and F1+2 levels were significant in the prediction of the presence of lymph node involvement on the multivariate logistic regression models (odds ratio 2502.081 (5.977-1047425.4); P = 0.010 and odds ratio 19.487 (1.495-253.936); P = 0.023, respectively). CONCLUSION: PT and plasma levels of F1+2 and D-dimer could be markers of degree or presence of lymph node involvement and clinical stage in patients with operable gastric cancer.
BMC Cancer. 2006 Jun 1;6:147. Hyperfibrinogenemia is associated with lymphatic as well as hematogenous metastasis and worse clinical outcome in T2 gastric cancer. Yamashita H, Kitayama J, Kanno N, Yatomi Y, Nagawa H.
BACKGROUND: Abnormal hemostasis in cancer patients has previously been described, however the correlation between the plasma fibrinogen level and cancer metastasis and prognosis has not been reported in a large-scale clinical study. METHODS: Preoperative plasma fibrinogen levels were retrospectively examined in 405 patients who underwent surgery for advanced gastric cancer. The association of fibrinogen levels with clinical/pathological findings and clinical outcome was evaluated. RESULTS: There was a positive correlation between plasma fibrinogen levels and the depth of invasion (p < 0.05). Hyperfibrinogenemia (>310 mg/dl) was independently associated with lymph node (Odds Ratio; 2.342, P = 0.0032) and liver (Odds Ratio; 2.933, P = 0.0147) metastasis, not with peritoneal metastasis in this series. Patients with hyperfibrinogenemia showed worse clinical outcome in T2 gastric cancer, however, there was no correlation of plasma fibrinogen level with prognosis in T3/T4 gastric cancer. CONCLUSION: Our results might support the idea that hyperfibrinogenemia can augment lymphatic and hematogeneous metastasis of advanced gastric cancer, which is major determinant of the prognosis in T2 gastric cancer. Therefore, in the situation without peritoneal involvement, hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome in T2 gastric cancer.
Jpn J Clin Oncol. 2005 Oct;35(10):595-600. Hyperfibrinogenemia is a useful predictor for lymphatic metastasis in human gastric cancer. Yamashita H, Kitayama J, Nagawa H.
BACKGROUND: Although abnormal hemostasis has been described in cancer patients, the precise association between the plasma fibrinogen level and lymphatic metastasis has not been reported in a large-scale clinical study. METHODS: Preoperative plasma levels of fibrinogen as well as C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were retrospectively examined in 649 patients who underwent surgery for gastric cancer, and the correlation between these factors and nodal status was evaluated. RESULTS: Plasma fibrinogen level in patients with gastric cancer showed a positive association with nodal classification (P < 0.0001). Hyperfibrinogenemia (>310 mg/dl) as well as high CEA (>5 ng/ml) and CRP (>0.3 mg/dl) showed a significant association with nodal metastasis in univariate analysis. Multivariate analysis revealed that hyperfibrinogenemia had an independent association with nodal metastasis (odds ratio, 2.004 (1.140-3.521); P = 0.0157), whereas CEA and CRP were not independent factors. Hyperfibrinogenemia showed an independent association even in advanced cancer [odds ratio 2.611 (1.404-4.854), P = 0.0024, n = 319]. When the 649 gastric cancers were classified into intestinal-type and gastric-type adenocarcinomas, plasma fibrinogen level was correlated with nodal metastasis only in the intestinal-type. CONCLUSIONS: Our results suggest that hyperfibrinogenemia may provide favorable circumstances for cancer cells to metastasize via the lymphatic system. Preoperative plasma fibrinogen level is a useful predictor of lymphatic metastasis in intestinal-type gastric cancer.
Hepatogastroenterology. 2004 Nov-Dec;51(60):1860-3. Preoperative plasma fibrinogen levels in gastric cancer patients correlate with extent of tumor. Lee JH, Ryu KW, Kim S, Bae JM.
BACKGROUND/AIMS: The aim of the present study was to investigate the relationship between the preoperative plasma fibrinogen level and the extent of tumor involvement in gastric cancer patients. METHODOLOGY: Preoperative plasma fibrinogen levels of 354 patients who underwent gastric cancer surgery were quantified using an immunoassay. The relationships between the plasma fibrinogen level and other prognostic variables (tumor size, macroscopic and histological type, depth of tumor invasion, presence of lymph node involvement and distant metastasis) were then examined using univariate and multivariate linear regression analyses. RESULTS: The plasma fibrinogen level was significantly lower in patients with early gastric cancer than in those with advanced gastric cancer (312+/-6.7 vs. 361.9+/-97.0 mg/mL, p<0.001). A significant relationship existed between the preoperative fibrinogen levels and the presence of metastatic lymph nodes (320+/-78.6 vs. 352.6+/-94.1 mg/mL, p=0.001) and distant metastasis (338.2+/-89.5 vs. 396.9+/-128.3 mg/mL, p=0.013). Size of the tumors and depth of tumor invasion could predict elevated fibrinogen levels positively in both the univariate regression and multivariate linear regression analyses. CONCLUSIONS: These data suggest that the plasma fibrinogen level is a clinically important and useful marker of the extent of tumor progression in gastric cancer.
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