The two-part article, "Thromboembolic Complications of Malignancy," by Drs. Linenberger and Wittkowsky, provides a contemporary and clear review of the pathogenesis, prevention, and treatment of cancer-associated hypercoagulability and venous thrombosis. Questions about the cancer and coagulation connection continue to abound and greatly outnumber evidence-based answers. As the relationship between cancer and coagulation gains attention from the medical and surgical oncology communities (ie, not only from the coagulation community), the gap between questions and answers will likely close. As described by the authors, human malignancies and their varied treatments can promote potent hypercoagulability and clinical thrombosis. The fact that thrombosis may have an impact on the cancer patient beyond simply leading to symptomatic, and at times, fatal thrombosis including pulmonary embolism is gaining attention from clinicians and basic scientists alike. Mechanisms
Thrombosis, and the accompanying vascular occlusion, may promote vascular growth factor release that can drive neovascularization locally as well as at distant sites. Coagulation activation by tumor cells via the tissue factor-factor VIIa (TF-VIIa) complex promotes thrombin and fibrin generation as well as angiogenesis via protease-activated receptor (PAR)-1 and PAR-2 signaling. Thus, primary and secondary prevention of venous thromboembolic events and tissue factor-mediated hypercoagulability may block or limit a known stimulus of tumor growth and metastasis. Based on this hypothesis, asymptomatic venous thromboses that are often considered to be unimportant may actually be as deleterious in the cancer patient as symptomatic events. Because of the harmful effects of thrombosis in the cancer patient, a zerotolerance attitude should be considered. That said, prophylaxis is used on a limited basis, primarily in the surgical on- cology setting. Currently available prophylaxis strategies are limited in terms of both safety and efficacy. An increased risk of bleeding in the cancer patient is perceived and real. The risk of bleeding, though, must exceed the risk of thrombosis to warrant withholding of prophylaxis. Just because patients with pronounced thrombocytopenia, central nervous system metastases, and hepatic insufficiency are at a heightened risk for bleeding, does not exclude them from being worthy candidates for venous thromboprophylaxis, albeit mechanical thromboprophylaxis. Pharmacologic regimens that will further reduce the risk of thrombosis in the cancer patient population are needed and will likely require the development of new drugs rather then simply the optimization of therapy with currently available drugs. Prevention Measures
The prevention of recurrent thrombosis is predicated on the timely diagnosis of the initial thrombosis and commencement of effective therapy. The index of suspicion for thrombosis in cancer patients must be high. Limb swelling in a patient with a pelvic mass may reflect extrinsic venous outflow obstruction but may also reflect acute deep-vein thrombosis. Exacerbation of dyspnea or chest pain in a lung cancer patient may reflect progression of the primary malignancy or reflect superimposed acute pulmonary embolism. Abdominal pain status post-colon cancer resection may reflect incisional pain or may reflect mesenteric or portal vascular thrombosis. In these situations, an objective diagnosis of thrombosis should be actively sought. Ideally, thrombosis in these clearly high-risk patients should be aggressively prevented. We need better anticoagulants in general and better anticoagulants specifically for use in patients with cancer. Attempts to identify particular coagulation cascade targets that will be optimal for thrombus prevention and possible metastasis and mortality reduction are ongoing. For example, targeting the TF-VIIa complex seems prudent. It is time for hypotheses to evolve into formal human clinical trials. Conclusions
The cancer and coagulation connection is becoming widely accepted but requires significant clarification. Only with further clinical evaluation will we be able to optimize the prevention and treatment of thrombosis in cancer patients. Preclinical antiangiogenesis and antimetastasis observations attributed to select anticoagulants require rigorous clinical study verification. I applaud the authors and referenced cancer and coagulation pioneers for a job well done.
Dr. Deitcher is an employee of Nuvelo.