Trousseau's syndrome: multiple definitions and multiple mechanisms

Abstract

In 1865, Armand Trousseau noted that unexpected or migratory thrombophlebitis could be a forewarning of an occult visceral malignancy. An analysis by Sack and colleagues in 1977 extended the term Trousseau's syndrome to include chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial emboli in patients with cancer, often occurring with mucin-positive carcinomas. In recent times the term has been ascribed to various clinical situations, ranging all the way from these classic descriptions to any kind of coagulopathy occurring in the setting of any kind of malignancy. These multiple definitions of Trousseau's syndrome are partly the consequence of multiple pathophysiologic mechanisms that apparently contribute to the hypercoagulability associated with cancer. Even the classic syndrome probably represents a spectrum of disorders, ranging from exaggerated fluid-phased thrombosis dependent on prothrombotic agents such as tissue factor to a platelet- and endotheliumum-based selectin-dependent microangiopathy associated with mucin-producing carcinomas, along with thrombin and fibrin production. Also considered here are recent hypotheses about genetic pathways within tumor cells that might trigger these thrombotic phenomena, and the reasons why therapy with heparins of various kinds remain the preferred treatment, probably because of their salutary actions on several of the proposed pathologic mechanisms.

Figure 1

Multiple mechanisms in Trousseau's syndrome. There are multiple overlapping and interacting mechanisms that can explain the increased incidence of thrombosis in patients with malignancies. In Trousseau's syndrome, hypercoagulability manifests even before the diagnosis of the tumor and is probably the result of products arising from the tumor itself. The most common malignancies associated with this syndrome are carcinomas (cancers of epithelial origin) that are often, but not always, mucin producing. This cartoon depicts a mucin-producing carcinoma arising in a hollow organ, which secretes mucins with altered glycans inappropriately into the bloodstream. Although the bulk of these mucins are probably rapidly cleared by the liver, a small fraction are resistant to clearance and can interact with P- and L-selectins, inducing the formation of platelet-rich microthrombi by multiple pathways. Exposure of tissue factor (TF)–rich tumor cell surfaces to the bloodstream or the release of TF-rich microvesicles by the tumor is presumed to induce fibrin formation and platelet aggregation by thrombin production. There is some evidence for a cysteine proteinase secreted by carcinoma cells that can directly activate factor X to generate thrombin. Although interactions of platelet and endothelial P-selectin with P-selectin glycoprotein ligand-1 (PSGL-1) on monocytes may further contribute to these reactions, the exact mechanism by which mucins eventually generate thrombin and fibrin production is unknown. Hypoxic conditions within the tumor, the expression of the MET oncogene, or both might also enhance production of procoagulant factors such as TF and plasminogen activator inhibitor-1 (PAI-1), and tumor-derived inflammatory cytokines may serve to activate endothelial and platelet adhesion molecules. Various combinations of these mechanisms can help explain the unusual, migratory, and exaggerated thrombotic phenomena of Trousseau's syndrome. As indicated in the figure, heparin has potential salutary effects on many of the relevant processes. This may explain why heparin preparations of various kinds are the preferred agent for the management of Trousseau's syndrome.