Decision Making in Venous Thromboembolism

Cancer-Associated Hypercoagulable State

Patients with cancer have a propensity for thromboembolic events. The underlying mechanisms responsible for cancer-associated clotting events are multifactorial and an area of intense research. Tumor cells can initiate activation of the clotting cascade through release of tissue factor and other pro-coagulant molecules [105].Type and stage of cancer impact risk of VTE, and the tumor itself can compress vasculature leading to venous stasis. Furthermore, chemotherapy, hormone therapy, antiangiogenic drugs, erythropoietin agents, and indwelling central venous catheters all are associated with increased risk of thrombotic events. Approximately 25% of all cancer patients will experience a thrombotic event during the course of their disease [106]. In fact, the presence of a spontaneous clot may be a harbinger of underlying malignancy [107].Approximately 10% of patients who present with an idiopathic VTE are diagnosed with cancer in the next 1 to 2 years.

The utility of extensive cancer screening in patients with spontaneous clotting events is often debated. The small studies that have addressed cancer associated clots have not demonstrated any mortality benefit with extensive screening. A prospective cohort study addressed the utility of limited versus extensive screening [108].In this study, all patients underwent a series of basic screening tests such as history taking, physical examination, chest radiograph, and basic laboratory parameters. Approximately half of the patients underwent additional testing (CT of chest and abdomen and mammography for women). Screening did not result in increased survival or fewer cancer-related deaths. 3.5 % of patients in the extensive screening group were diagnosed with malignancy in comparison to 2.4% in the limited screening group. During follow-up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. The authors concluded that the low yield of extensive screening and lack of survival benefit did not warrant routinely ordering cancer screening tests above and beyond age-appropriate screening in patients with idiopathic VTE. However, it is known that identification of occult malignancy at an earlier stage of disease is beneficial, and cancer diagnosed within one year of an episode of VTE is generally more advanced and associated with a poorer prognosis [109].It is our practice to take a through history from patients with unprovoked clots particularly focusing on symptoms suggestive of an underlying cancer. We recommend that patients be up to date with all age-appropriate cancer screening.

Heparin-based products (rather than warfarin) are recommended for long-term treatment of cancer-associated DVT. Several trials, most prominently the CLOT trial, have demonstrated that LMWH is associated with reduced risk of recurrent VTE compared with warfarin in cancer patients [110].Fondaparinux may be a reasonable alternative if a patient is unable to tolerate a LMWH. In terms of treatment duration, patients with cancer-associated VTE should be anticoagulated indefinitely as long as they continue to have evidence of active malignancy and/or remain on antineoplastic treatment [111].

Heparin has potential anticancer effects beyond its anticoagulation properties. It is believed that heparin use in patients with cancer can influence cancer progression by acting as an antimetastatic agent. The molecular mechanisms underlying this significant observation are not completely understood, although the first documented benefit of these drugs dates back to the 1970s [112].Overall, LMWH have been associated with improved overall survival in cancer patients and this effect appears to be distinct from its ability to prevent life-threatening VTE episodes [113].