Course Authors
Leo Zacharski, M.D., and Robert G. Lerner, M.D.
Dr. Zacharski is Professor of Medicine, Dartmouth Medical School, Hanover, New Hampshire, and Associate Chief of Staff, VA Medical Center, White River Junction, Vermont.
In the past three years, Dr. Zacharski has received support from the Department of Veterans Affairs Medical Research Service, and has been on the Speakers' Bureau for Dupont Pharmaceutical and Aventis. In the past three years, Dr. Lerner has served as a consultant for RPR, and has served on the Speakers' Bureau for Pharmacia & Upjohn.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe "warfarin resistant" DVT in cancer patients
Describe several mechanisms by which heparin could alter tumor progression
Evaluate, critically, new data on the effect of heparin and LMWH on cancer.
Background
Considerable data have implicated coagulation mechanisms in the pathogenesis of malignancy. Specifically, the familiar anticoagulant, heparin, has properties that may effect tumor growth. Heparin may modify angiogenesis,(1) growth factors,(2) protease activity,(3) immune function,(4) cell proliferation(5) and gene expression(6) that contribute to tumor progression. Heparin has anti-tumor effects in animal models of malignancy(7) and studies in human malignancy have also provided evidence for improvement in cancer outcome with heparin treatment.(8) The following case illustrates some interesting points about cancer and coagulation.
Case Report
A 79-year-old married woman presented with a two-month history of gradually progressive anorexia, fatigue, and dry cough. She had otherwise been well all of her life, had never smoked, and had been physically active up to that time. Upon arising on the day of admission, she noted sudden onset of pain and swelling of her right leg, a feeling of breathlessness and pain with breathing over the left posterior chest. Physical examination revealed enlarged left supraclavicular lymph nodes. Chest X-ray showed a four-centimeter mass in the left mid-lung field posteriorly, a small left pleural effusion and enlargement of the mediastinal lymph nodes on the left.
Vascular testing by duplex Doppler and spiral CT revealed deep vein thrombosis of the right femoral vein and a pulmonary embolism in the left mid lung field. Biopsy of a left supraclavicular node revealed metastatic adenocarcinoma of the lung. She was treated in the hospital with intravenous unfractionated heparin followed by warfarin. The patient declined treatment with chemotherapy and she was not considered a candidate for radiation therapy. Her symptoms improved and she was discharged from the hospital on warfarin at an INR of 2.4. However, she was readmitted one month later and diagnosed as having recurrent thrombosis, which was, this time, in the left femoral vein. Two interim prothrombin time determinations indicated that she had been well controlled on warfarin and her INR on admission was 3.1. She was treated again with intravenous heparin with resolution of symptoms.
She was discharged on 40 mg of enoxaparin per day that she gave by injection to herself. (It should be noted here that this dose of enoxaparin is considered a prophylactic dose, not a therapeutic dose, and is not recommended for long term treatment of DVT.) She returned home to be followed by her local physician. One year later, she was referred for re-evaluation. She had continued to lead an active life in the interim and had noted only a mild increase in shortness of breath with exertion. She had had no further episodes of venous thrombosis. Otherwise, she had been feeling relatively well. Her physical examination was unchanged. Chest X-ray showed that her left lung mass and mediastinal nodes were approximately the same but the left pleural effusion had increased. Injection of daily low molecular weight heparin at the prophylactic dose of 40 mg/day was continued.
Discussion
Two points are illustrated by this case. One is the concept of warfarin-resistant DVT with malignancy. Another is the possible contribution of the coagulation mechanism to tumor progression that was inhibited by her heparin treatment. It is conceivable that chronic treatment with low molecular weight heparin may have retarded tumor growth because of its ability to inhibit angiogenesis and the activity of certain growth factors necessary for tumor growth.
This patient appears to have had warfarin-resistant DVT since she had a recurrence of DVT while treated with warfarin with an INR in the therapeutic range. She subsequently survived for more than a year without a recurrence of DVT while receiving enoxaparin, a low molecular weight heparin. This pattern of warfarin-resistant DVT with malignancy is well recognized.(9) It has been proposed that tumors induce coagulation activation either directly, by expression of tumor cell procoagulants, or indirectly, by activating macrophages that express procoagulants.(10) In either case, the procoagulant is likely to be tissue factor.(11)
Tissue factor is a tissue protein that serves as the normal extravascular surface protein that initiates hemostasis by interacting with coagulation Factor VII. This very intense activation coagulation may be difficult to inhibit by using warfarin that lowers the concentration of coagulation factors but does not directly inhibit coagulation. Such coagulation activation is much more effectively inhibited by an anticoagulant such as heparin and, perhaps, even more so by the smaller low-molecular-weight-heparin-antithrombin complex. Evidence to support this hypothesis is available. Patients with DVT have had a lower recurrence rate when treated with the tinzaparin, a low-molecular weight-heparin, when compared to standard unfractionated heparin.(12) A retrospective meta-analysis of the data from several treatment trials reveals that this difference is especially noted in cancer patients. The authors also note that there is preliminary evidence that LMWH treatment prolongs survival and recommend that low-molecular-weight heparin be used as the initial therapy of venous thromboembolism in patients with cancer.(13)
This case also illustrates the contribution of the coagulation mechanism to tumor progression and the possibility that it was inhibited by her heparin treatment. Tumor metastases are typically surrounded by a zone of fibrin that may be important for the growth of the tumor and the generation of new blood vessels to supply the tumor. Heparin can inhibit the fibrin formation and directly inhibit angiogenesis.(1) Both heparin and LMWH may also inhibit tumor growth by inhibiting the activity of growth factors.(14) Whatever the mechanism, this woman had stabilization of her lung cancer for a year.
There are other activities of heparin that may have contributed to the stabilization of the cancer. Heparin can also affect immune mechanisms controlling cancer through an effect on interferon.(15) A heparin effect on malignant cell proliferation has also been described.(16) Gene expression can also be influenced by heparin(6) and this effect may have contributed to the patient's tumor stabilization.
Whatever the molecular mechanism involved, heparin has been shown to have direct anti-tumor activity in animal models of malignancy, as well as studies in human malignancy.(17) In rats with implanted cancer, treatment with heparin has decreased the number of metastases. In human malignancy, prospective trials have shown a prolongation of survival but an analysis has questioned the significance of the data.(18)
Summary
This case illustrates many possible interactions between heparin and cancer that may have come into play during the course of the patient's disease. Clinical trials and basic investigations in the area will have to be carried out if we are to maximize the usefulness of this knowledge in our treatment of cancer patients.
The investigation of the coagulation-heparin-cancer interaction is hindered by certain problems. Cancer is heterogeneous. Mechanisms at play clinically are poor indicators. Many other factors influence outcome. However, evidence for clinically useful efficacy is present and must be evaluated by future investigation.