A 67-year-old woman presented to the ED with right lower-extremity swelling. She initially felt a sharp pain in the popliteal region of her right leg a week prior to presentation. Her medical history consisted of clear-cell ovarian cancer (currently treated with bevacizumab and carboplatin), hypertension, and anxiety. She had no history of venous thromboembolism and no family history of thrombophilia. The patient did not smoke or drink alcohol. Outpatient medications included hydrochlorothiazide, lisinopril, alprazolam, bevacizumab, and carboplatin.
The patient was not in acute distress and was afebrile, with a blood pressure of 169/81 mm Hg, a heart rate of 81 beats/min, a respiratory rate of 16 breaths/min, and oxygen saturation of 99%. Physical exam was remarkable for a swollen right lower extremity with tenderness to palpation. The remainder of her exam was normal. Admission labs revealed a hemoglobin level of 11.4 g/dL, a white blood cell count of 6,000 cells/mm3, and a platelet count of 265,000 cells/mm3. Blood chemistries revealed a sodium level of 125 mEq/L and a chloride level of 86 mEq/L; the remainder were normal. An ultrasound of the right lower extremity demonstrated an occlusive thrombus within the mid- and distal right femoral, popliteal, and calf veins. The patient was started on subcutaneous enoxaparin. She was discharged home two days after admission on enoxaparin, 80 mg subcutaneously daily, with plans for anticoagulation indefinitely.
Background and pathophysiology
Venous thromboembolism (VTE) can be a complication of a known cancer or the presenting symptom of an occult malignancy. Patients with a VTE have more than a fourfold increased risk for cancer compared with the general population (1). In patients with a known malignancy, the annual incidence of VTE is 1 in 200 (2). Not only does VTE lead to a threefold increase in hospitalizations, it is also the second leading cause of death in patients with malignancy (3).
The underlying mechanism behind the thrombogenic nature of cancer is complex. Cancer cells activate the coagulation cascade through their direct influence on blood cells and vasculature (4). In addition, the cancer cells also produce procoagulant factors and pro-inflammatory cytokines (4).
Patients with malignancy have increased levels of factors V, VIII, IX, and XI; however, increased tissue factor (TF) expression has the greatest association with cancer-related VTE (4, 5, 6). Cytokines produced by the cancer cells, such as tumor necrosis factor-alpha and interleukin-1 beta, induce TF expression (4). Fibrin, a procoagulant factor, also increases TF expression by up-regulating vascular endothelial growth factor and interleukin-8 (4). Increased levels of TF lead to activation of the extrinsic clotting cascade as well as activation of the mitogen-activated protein kinase signal transduction cascade, which induces genes involved in angiogenesis, migration, and proliferation (4).
A strong association between TF and the hypercoagulable state of cancer has been demonstrated, due to the mechanisms described above. Increased TF expression occurs early in malignancy and in a variety of tumor types, although it has been most reported in pancreatic cancer (6). In a subgroup analysis of one study, elevated TF at the initial VTE event was found to be predictive of recurrent VTE in patients who receive appropriate anticoagulation (6). Future studies are needed to validate this conclusion and determine the optimal method and timing for measuring TF.
Although cancer has broadly been identified as a risk factor for VTE, specific factors of malignancy are associated with increased risk. First, a patient's thrombotic risk is influenced heavily by the type of malignancy, with the highest risk being mucin-producing adenocarcinomas, specifically ovarian, pancreas, lung, stomach, and adenocarcinomas of unknown primary cause (1, 2, 7).
In addition, chemotherapy can further increase the risk of VTE to as much as 6.5 times normal, compared to a 4.1-fold increase with malignancy alone (7). Traditionally, treatments that have the highest association with VTE include drugs targeting angiogenesis (bevacizumab, sunitinib, sorafenib), immunomodulators (thalidomide, lenalidomide), and antiepidermal growth factor antibodies (cetuximab, panitumumab) (3, 5).
Several predictive models have been developed to risk-stratify patients. The Khorana score (7) is the most validated model, incorporating factors such as the site of cancer, prechemotherapy platelet count of 350 × 109 cells/L or more, hemoglobin level below 10 g/dL or use of red cell growth factors, prechemotherapy leukocyte count above 11 × 109 cells/L, and a body mass index of 35 kg/m2 or higher. The scoring system divides patients into three risk groups to help clinicians determine whether to initiate VTE prophylaxis. Scores of 3 or greater indicate the highest risk.
Routine prophylaxis against VTE in patients with malignancy is controversial. In ambulatory patients, the routine use of prophylaxis is discouraged by guidelines (8). If the patient has a high-risk cancer (Khorana score of 3 or more or advanced pancreatic cancer) or is receiving an immunomodulatory drug-based regimen for myeloma treatment or another highly thrombogenic chemotherapy, prophylaxis should be considered (3, 5, 8).
Other factors that would place patients without a malignancy at higher risk of VTE, such as acute illness resulting in hospitalization or surgery, also require prophylaxis. Patients with malignancy who are hospitalized should receive VTE prophylaxis with low-molecular-weight heparin (LMWH) unless they are at increased risk for hemorrhage or have other contraindications (8). Two randomized controlled trials have suggested that patients who undergo surgery for pelvic or abdominal malignancy should receive prophylactic anticoagulation 30 days postoperatively (9, 10).
Treatment and follow-up
A guideline from the American Society of Clinical Oncology (ASCO) recommends LMWH over vitamin K antagonists, direct thrombin inhibitors, or factor Xa inhibitors for treatment of VTE in patients with malignancy (8, 11). In patients with renal impairment (creatinine clearance <30 mL/min), ASCO suggests that unfractionated heparin or vitamin K antagonists may be a safer option to prevent bleeding risks as LMWH can accumulate over time and anti-factor Xa monitoring is typically not readily available (8, 12). If factor Xa levels cannot be easily monitored, vitamin K antagonists are likely a safer option, although few studies have evaluated long-term effects (12).
Several randomized trials have evaluated the efficacy of LMWH versus vitamin K antagonists. In the CLOT trial, dalteparin was compared to warfarin and associated with a significantly lower risk of symptomatic recurrent thromboembolism in patients with active cancer (13). More recently, the CATCH trial compared tinzaparin and warfarin and found no statistically significant difference between full-dose tinzaparin and warfarin (14). This study had a lower than predicted thrombotic event rate in the warfarin group, as well as fewer patients with metastatic disease, receiving active chemotherapy, or with a previous VTE than the CLOT trial, which may account for this difference (14). There have been no head-to-head comparisons of the various LMWHs.
There are also no randomized controlled trials comparing the direct thrombin inhibitors or factor Xa inhibitors with LMWH for treatment of VTE in patients with malignancy. A meta-analysis using data from the RECOVER, EINSTEIN-DVT/PE, and HOKUSAI-VTE trials demonstrated that direct thrombin inhibitors or factor Xa inhibitors are at least comparable to vitamin K antagonists for the outcomes of recurrent VTE or bleeding events (15). Although patients were identified as having cancer, it is unknown whether they had active malignancy or were undergoing chemotherapy (15). Further studies comparing the direct thrombin inhibitors or factor Xa inhibitors to LMWH are needed.
According to ASCO guidelines, anticoagulation should be continued for at least six months after the initial VTE (8). After six months, patients who are at high risk for recurrent VTE, such as those undergoing active chemotherapy or those with metastatic disease, should continue anticoagulation (8).