Cancer, Clots and Consensus: New Understanding of an Old Problem

Long before reaching our current understanding of the complex relationship between malignancy and the elements of the coagulation system, it was recognized that patients with cancer were at increased risk for thrombosis. Armand Trousseau first described patients with thrombophlebitis as the presenting sign of a visceral malignancy, later known as Trousseau’s syndrome, which he attributed to a special alteration of the blood. Increased risk of thrombosis is associated with alterations in normal blood flow, injury to the vascular endothelium, and alterations in the constitution of blood, referred to as Virchow’s triad (Table 1). While the resulting hypercoagulable state rarely results in overt disseminated intravascular coagulation, virtually all patients with active malignancy demonstrate some degree of activation of the coagulation cascade. Today, it is recognized that thrombosis and cancer are linked by multiple pathophysiological mechanisms and that tumor biology and coagulation processes are integrally connected (Fig 1). The underlying biologic factors associated with the increased risk of thrombosis in patients with cancer include the activation of thrombin and fibrin formation both directly by the release of procoagulants by tumor cells and indirectly by the activation of endothelial cells, leukocytes, and platelets by cytokines and the production of a factor X-activating cysteine protease, mucinous glycoproteins, and circulating tissue factor–bearing microparticles. The molecular and genomic factors at the interface between malignant cell behavior and the hypercoagulable state in the patient with cancer are discussed in the articles by Boccaccio and Comoglio and by Kasthuri et al in this special issue of the Journal of Clinical Oncology. Venous thromboembolism (VTE) may indicate an occult cancer, may represent a complication of a known malignancy, or complicate hospitalization, surgery, or various systemic cancer treatments. VTE, including deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and potentially life-threatening disorder representing the second leading cause of death in hospitalized patients with cancer, although often demonstrated only at autopsy. In addition, the occurrence of VTE may interrupt needed cancer treatment, even as the use of anticoagulants may result in serious bleeding complications. In addition to the human cost, the economic burden of VTE in patients with cancer is substantial with the average cost of hospitalization for DVT estimated at more than $20,000 and one fourth of patients with cancer with VTE requiring readmission as a result of bleeding or a recurrent VTE. Fortunately, there has been considerable progress not only in our basic understanding of the underlying pathophysiology, but also in the diagnosis of VTE and the options available for the treatment and prevention of thrombosis in patients with cancer. Current guidelines recommend primary prophylaxis in both surgical and medical hospitalized patients and for highly selected ambulatory patients with cancer. The development and validation of clinical risk models and the identification of new biomarkers for the selection of patients at increased risk for VYE represents an active area of research. Likewise, the potential impact of anticoagulation on cancer growth, invasion, metastases, and angiogenesis as well as overall survival continues to be actively investigated. It is essential that the results of ongoing research on underlying mechanisms as well as the optimal treatment Procoagulant activities Fibrinolytic activities